Substitued benzofuran compounds and methods of use thereof for the treatment of viral diseases

ABSTRACT

The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.

FIELD OF THE INVENTION

The present invention relates to novel Substituted Benzofuran Compounds,compositions comprising at least one Substituted Benzofuran Compound,and methods of using the Substituted Benzofuran Compounds for treatingor preventing HCV infection in a patient.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) infection is a major health problem that leadsto chronic liver disease, such as cirrhosis and hepatocellularcarcinoma, in a substantial number of infected individuals. Currenttreatments for HCV infection include immunotherapy with recombinantinterferon-α alone or in combination with the nucleoside analogribavirin.

Several virally-encoded enzymes are putative targets for therapeuticintervention, including a metalloprotease (NS2-3), a serine protease(NS3, amino acid residues 1-180), a helicase (NS3, full length), an NS3protease cofactor (NS4A), a membrane protein (NS4B), a zincmetalloprotein (NS5A) and an RNA-dependent RNA polymerase (NS5B).

HCV NS5B polymerase is described, for example, in Behrens et al., EMBOJ. 15(1) 12-22 (1996). Antagonists of NS5B activity are known to beinhibitors of HCV replication. See Carroll et al., J. Biol. Chem.278(14) 11979-84 (2003).

There is a clear and long-felt need to develop effective therapeuticsfor treatment of HCV infection. Specifically, there is a need to developcompounds that selectively inhibit HCV viral replication and that wouldbe useful for treating HCV-infected patients.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides Compounds of Formula (I)

and pharmaceutically acceptable salts thereof, wherein:

A is:

wherein A can be joined to the benzofuran moiety of formula (I) via anyof group A's ring carbon atoms;

L is N or CH;

M is N or CH;

Q is —CH(R^(4b));

U is —N(R⁵)—, O, S or —C(R^(4b))₂—;

V is —N— or —C(R^(4a))—;

W is —N— or —C(R⁴)—, or the group —W═V—U— is —NH—C(O)—N(R⁵)—

one of Y¹ and Y² is —N— or —C(R¹⁰)—, and the other of Y¹ and Y² is acarbon atom and represents the point of attachment of the benzofuranmoiety depicted in formula (I);

X and Z are each independently —N— or —C(R¹⁰)—;

R¹ represents up to 4 optional ring substituents, which can be the sameor different, and are independently selected from halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl) and —CN;

R² is —C(O)N(R⁶)(R⁷);

R³ is 5 or 6-membered heterocycloalkyl or —N(R⁸)—S(O)_(n)—R⁹, whereinsaid 5 or 6-membered heterocycloalkyl can optionally have one of itsring carbon atoms replaced with a carbonyl group;

R⁴ is selected from H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), C₁-C₆ hydroxyalkyl, —C(O)O—(C₁-C₆ alkyl),—(C₁-C₆ alkylene)_(r)-aryl, —(C₁-C₆ alkylene)_(r)-(3 to 7-memberedmonocyclic cycloalkyl), —(C₁-C₆ alkylene)_(r)-(4 to 7-memberedmonocyclic heterocycloalkyl), —(C₁-C₆ alkylene)_(n)-(5 or 6-memberedmonocyclic heteroaryl) and —(C₁-C₆ alkylene)_(r)-(9 or 10-memberedbicyclic heteroaryl), wherein said aryl group, said 3 to 7-memberedmonocyclic cycloalkyl group, said 4 to 7-membered monocyclicheterocycloalkyl group, said 5 or 6-membered monocyclic heteroaryl groupand said 9 or 10-membered bicyclic heteroaryl group can be optionallysubstituted with up to 3 groups, which can be the same or different, andare selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, 3 to7-membered monocyclic cycloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —S(O)₂—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆ alkyl), C₁-C₆hydroxyalkyl and —CN;

R^(4a) is selected from H, C₁-C₆ alkyl, 3 to 7-membered cycloalkyl,phenyl and 5 or 6-membered monocyclic heteroaryl, wherein said 3 to7-membered cycloalkyl group, said phenyl group and said 5 or 6-memberedmonocyclic heteroaryl group can be optionally substituted with up to 2groups, which can be the same or different, and are selected from C₁-C₆alkyl, C₁-C₆ haloalkyl, halo, —CN, —O—(C₁-C₆ alkyl) and —O—(C₁-C₆haloalkyl);

each occurrence of R^(4b) is independently selected from H, C₁-C₆ alkyl,3 to 7-membered cycloalkyl, phenyl and 5 or 6-membered monocyclicheteroaryl, wherein said 3 to 7-membered cycloalkyl group, said phenylgroup and said 5 or 6-membered monocyclic heteroaryl group can beoptionally substituted with up to 2 groups, which can be the same ordifferent, and are selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, halo,—CN, —O—(C₁-C₆ alkyl) and —O—(C₁-C₆ haloalkyl);

each occurrence of R⁵ is independently selected from H, C₁-C₆ alkyl,C₁-C₆ hydroxyalkyl, —C(O)O—(C₁-C₆ alkyl), —(C₁-C₆ alkylene)_(r)-phenyl,—(C₁-C₆ alkylene)_(r)-(3 to 7-membered monocyclic cycloalkyl), —(C₁-C₆alkylene)_(r)-(4 to 7-membered monocyclic heterocycloalkyl), —(C₁-C₆alkylene)_(r)-(5 or 6-membered monocyclic heteroaryl) and —(C₁-C₆alkylene)_(r)-(9 or 10-membered bicyclic heteroaryl), wherein saidphenyl group, said 3 to 7-membered monocyclic cycloalkyl group, said 4to 7-membered monocyclic heterocycloalkyl group, said 5 or 6-memberedmonocyclic heteroaryl group and said 9 or 10-membered bicyclicheteroaryl group can be optionally substituted with up to 3 groups,which can be the same or different, and are selected from halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —S(O)₂—C₁-C₆ alkyl,—C(O)O—(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl and —CN;

R⁶ and R⁷ are each independently selected from hydrogen, C₁-C₆ alkyl,phenyl, 3 to 7-membered monocyclic cycloalkyl, 3 to 7-memberedmonocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl;and

R⁸ is selected from H, C₁-C₆ alkyl and 3 to 7-membered monocycliccycloalkyl;

R⁹ is selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, 3 to7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclicheterocycloalkyl and 5 or 6-membered monocyclic heteroaryl;

each occurrence of R¹⁰ is independently selected from H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl) and —CN;

each occurrence of n is independently 1 or 2; and

each occurrence of r is independently 0 or 1.

The Compounds of Formula (I) (also referred to herein as the“Substituted Benzofuran Compounds”) and pharmaceutically acceptablesalts thereof can be useful, for example, for inhibiting HCV viralreplication or replicon activity, and for treating or preventing HCVinfection in a patient. Without being bound by any specific theory, itis believed that the Substituted Benzofuran Compounds inhibit HCV viralreplication by inhibiting HCV NS5B.

Accordingly, the present invention provides methods for treating orpreventing HCV infection in a patient, comprising administering to thepatient an effective amount of at least one Substituted BenzofuranCompound.

The details of the invention are set forth in the accompanying detaileddescription below.

Although any methods and materials similar to those described herein canbe used in the practice or testing of the present invention,illustrative methods and materials are now described. Other embodiments,aspects and features of the present invention are either furtherdescribed in or will be apparent from the ensuing description, examplesand appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel Substituted Benzofuran Compounds,compositions comprising at least one Substituted Benzofuran Compound,and methods of using the Substituted Benzofuran Compounds for treatingor preventing HCV infection in a patient.

DEFINITIONS AND ABBREVIATIONS

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. If a chemical compound is referred tousing both a chemical structure and a chemical name and an ambiguityexists between the structure and the name, the structure is understoodto predominate. These definitions apply regardless of whether a term isused by itself or in combination with other terms, unless otherwiseindicated. Hence, the definition of “alkyl” applies to “alkyl” as wellas the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,” “—O-alkyl,” etc.. . .

As used herein, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a chimpanzee.

The term “effective amount” as used herein means that amount of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.In one embodiment, the effective amount is a “therapeutically effectiveamount” for the alleviation of one or more symptoms of the disease orcondition being treated. In another embodiment, the effective amount isa “prophylactically effective amount” for reduction of the severity orlikelihood of one or more symptoms of the disease or condition. Inanother embodiment, the effective amount is a “therapeutically effectiveamount” for inhibition of HCV viral replication and/or HCV viralproduction. The term also includes herein the amount of active compoundsufficient to inhibit HCV NS5B activity and thereby elicit the responsebeing sought (i.e., an “inhibition effective amount”). When the activecompound (i.e., active ingredient) is administered as the salt,references to the amount of active ingredient are to the free acid orfree base form of the compound.

The term “preventing,” as used herein with respect to an HCV viralinfection or HCV-virus related disorder, refers to reducing thelikelihood of HCV infection.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup having one of its hydrogen atoms replaced with a bond. An alkylgroup may be straight or branched and contain from about 1 to about 20carbon atoms. In one embodiment, an alkyl group contains from about 1 toabout 12 carbon atoms. In different embodiments, an alkyl group containsfrom 1 to 6 carbon atoms (C₁-C₆ alkyl) or from about 1 to about 3 carbonatoms (C₁-C₃ alkyl). Non-limiting examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl andneohexyl. An alkyl group may be unsubstituted or substituted by one ormore substituents which may be the same or different, each substituentbeing independently selected from the group consisting of halo, alkenyl,alkynyl, aryl, cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl,-alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂,—NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)— cycloalkyl,—C(O)OH and —C(O)O-alkyl. In one embodiment, an alkyl group is linear.In another embodiment, an alkyl group is branched. Unless otherwiseindicated, an alkyl group is unsubstituted.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and having oneof its hydrogen atoms replaced with a bond. An alkenyl group may bestraight or branched and contain from about 2 to about 15 carbon atoms.In one embodiment, an alkenyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkenyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groupsinclude ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl,octenyl and decenyl. An alkenyl group may be unsubstituted orsubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy,—O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl),—N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. The term “C₂-C₆ alkenyl”refers to an alkenyl group having from 2 to 6 carbon atoms. Unlessotherwise indicated, an alkenyl group is unsubstituted.

The term “alkynyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon triple bond and having oneof its hydrogen atoms replaced with a bond. An alkynyl group may bestraight or branched and contain from about 2 to about 15 carbon atoms.In one embodiment, an alkynyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkynyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groupsinclude ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An alkynylgroup may be unsubstituted or substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkenyl, alkynyl, aryl,cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl,alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)—alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. Theterm “C₂-C₆ alkynyl” refers to an alkynyl group having from 2 to 6carbon atoms. Unless otherwise indicated, an alkynyl group isunsubstituted.

The term “alkylene,” as used herein, refers to an alkyl group, asdefined above, wherein one of the alkyl group's hydrogen atoms has beenreplaced with a bond. Non-limiting examples of alkylene groups include—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)—and —CH₂CH(CH₃)CH₂—. In one embodiment, an alkylene group has from 1 toabout 6 carbon atoms. In another embodiment, an alkylene group isbranched. In another embodiment, an alkylene group is linear. In oneembodiment, an alkylene group is —CH₂—. The term “C₁-C₆ alkylene” refersto an alkylene group having from 1 to 6 carbon atoms.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to about10 carbon atoms. An aryl group can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein below. In one embodiment, an aryl group can beoptionally fused to a cycloalkyl or cycloalkanoyl group. Non-limitingexamples of aryl groups include phenyl and naphthyl. In one embodiment,an aryl group is phenyl. Unless otherwise indicated, an aryl group isunsubstituted.

The term “cycloalkyl,” as used herein, refers to a non-aromatic mono- ormulticyclic ring system comprising from about 3 to about 10 ring carbonatoms. In one embodiment, a cycloalkyl contains from about 5 to about 10ring carbon atoms. In another embodiment, a cycloalkyl contains fromabout 3 to about 7 ring atoms. In another embodiment, a cycloalkylcontains from about 5 to about 7 ring atoms. In another embodiment, acycloalkyl contains from about 5 to about 6 ring atoms. The term“cycloalkyl” also encompasses a cycloalkyl group, as defined above,which is fused to an aryl (e.g., benzene) or heteroaryl ring.Non-limiting examples of monocyclic cycloalkyls include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl,norbornyl and adamantyl. A cycloalkyl group can be optionallysubstituted with one or more “ring system substituents” which may be thesame or different, and are as defined herein below. In one embodiment, acycloalkyl group is unsubstituted. The term “3 to 7-membered cycloalkyl”refers to a cycloalkyl group having from 3 to 7 ring carbon atoms.Unless otherwise indicated, a cycloalkyl group is unsubstituted. A ringcarbon atom of a cycloalkyl group may be functionalized as a carbonylgroup. An illustrative example of such a cycloalkyl group (also referredto herein as a “cycloalkanoyl” group) includes, but is not limited to,cyclobutanoyl:

The term “cycloalkenyl,” as used herein, refers to a non-aromatic mono-or multicyclic ring system comprising from about 4 to about 10 ringcarbon atoms and containing at least one endocyclic double bond. In oneembodiment, a cycloalkenyl contains from about 4 to about 7 ring carbonatoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms.

Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl,cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A cycloalkenyl groupcan be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein below. A ring carbon atom of a cycloalkyl group may befunctionalized as a carbonyl group. In one embodiment, a cycloalkenylgroup is cyclopentenyl. In another embodiment, a cycloalkenyl group iscyclohexenyl. The term “4 to 7-membered cycloalkenyl” refers to acycloalkenyl group having from 4 to 7 ring carbon atoms. Unlessotherwise indicated, a cycloalkenyl group is unsubstituted.

The term “halo,” as used herein, means —F, —Cl, —Br or —I.

The term “haloalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a halogen. In one embodiment, a haloalkyl grouphas from 1 to 6 carbon atoms. In another embodiment, a haloalkyl groupis substituted with from 1 to 3 F atoms. Non-limiting examples ofhaloalkyl groups include —CH₂F, —CHF₂, —CF₃, —CH₂Cl and —CCl₃. The term“C₁-C₆ haloalkyl” refers to a haloalkyl group having from 1 to 6 carbonatoms.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with an —OH group. In one embodiment, a hydroxyalkylgroup has from 1 to 6 carbon atoms. Non-limiting examples ofhydroxyalkyl groups include —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH and—CH₂CH(OH)CH₃. The term “C₁-C₆ hydroxyalkyl” refers to a hydroxyalkylgroup having from 1 to 6 carbon atoms.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising about 5 to about 14 ring atoms,wherein from 1 to 4 of the ring atoms is independently O, N or S and theremaining ring atoms are carbon atoms. In one embodiment, a heteroarylgroup has 5 to 10 ring atoms. In another embodiment, a heteroaryl groupis monocyclic and has 5 or 6 ring atoms. In another embodiment, aheteroaryl group is bicyclic and has 9 or 10 ring atoms. A heteroarylgroup can be optionally substituted by one or more “ring systemsubstituents” which may be the same or different, and are as definedherein below. A heteroaryl group is joined via a ring carbon atom, andany nitrogen atom of a heteroaryl can be optionally oxidized to thecorresponding N-oxide. The term “heteroaryl” also encompasses aheteroaryl group, as defined above, which is fused to a benzene ring.The term “heteroaryl” also encompasses any fused polycyclic ring systemcontaining at least one ring heteroatom selected from N, O and S,wherein at least one ring of the fused polycyclic ring system isaromatic. For example, the term “9 to 10-membered bicyclic heteroaryl”encompasses a non-aromatic 5 membered heterocyclic ring that is fused toa benzene or pyridyl ring. Non-limiting examples of heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl,thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and allisomeric forms thereof. The term “heteroaryl” also refers to partiallysaturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In oneembodiment, a heteroaryl group is a 5-membered heteroaryl. In anotherembodiment, a heteroaryl group is a 6-membered heteroaryl. In anotherembodiment, a heteroaryl group comprises a 5- to 6-membered heteroarylgroup fused to a benzene ring. Unless otherwise indicated, a heteroarylgroup is unsubstituted.

The term “heterocycloalkyl,” as used herein, refers to a non-aromaticsaturated monocyclic or multicyclic ring system comprising 3 to about 11ring atoms, wherein from 1 to 4 of the ring atoms are independently O,S, N or Si, and the remainder of the ring atoms are carbon atoms. Aheterocycloalkyl group can be joined via a ring carbon, ring siliconatom or ring nitrogen atom. In one embodiment, a heterocycloalkyl groupis monocyclic and has from about 3 to about 7 ring atoms. In anotherembodiment, a heterocycloalkyl group is monocyclic has from about 4 toabout 7 ring atoms. In another embodiment, a heterocycloalkyl group ismonocyclic has from about 5 to about 7 ring atoms. In anotherembodiment, a heterocycloalkyl group is bicyclic and has from about 7 toabout 11 ring atoms. In still another embodiment, a heterocycloalkylgroup is monocyclic and has 5 or 6 ring atoms. In one embodiment, aheterocycloalkyl group is monocyclic. In another embodiment, aheterocycloalkyl group is bicyclic. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Any —NH group in aheterocycloalkyl ring may exist protected such as, for example, as an—N(BOC), —N(Cbz), —N(Tos) group and the like; such protectedheterocycloalkyl groups are considered part of this invention. The term“heterocycloalkyl” also encompasses a heterocycloalkyl group, as definedabove, which is fused to an aryl (e.g., benzene) or heteroaryl ring. Aheterocycloalkyl group can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein below. The nitrogen or sulfur atom of theheterocycloalkyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclicheterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone,silacyclopentane, silapyrrolidine and the like, and all isomers thereof.Non-limiting illustrative examples of a silyl-containingheterocycloalkyl group include:

A ring carbon atom of a heterocycloalkyl group may be functionalized asa carbonyl group. An illustrative example of such a heterocycloalkylgroup is:

In one embodiment, a heterocycloalkyl group is a 5-membered monocyclicheterocycloalkyl. In another embodiment, a heterocycloalkyl group is a6-membered monocyclic heterocycloalkyl. The term “3 to 7-memberedmonocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl grouphaving from 3 to 7 ring atoms. The term “4 to 7-membered monocycliccycloalkyl” refers to a monocyclic heterocycloalkyl group having from 4to 7 ring atoms. The term “5 to 7-membered monocyclic cycloalkyl” refersto a monocyclic heterocycloalkyl group having from 5 to 7 ring atoms.The term “7 to 11-membered bicyclic heterocycloalkyl” refers to abicyclic heterocycloalkyl group having from 7 to 11 ring atoms. Unlessotherwise indicated, an heterocycloalkyl group is unsubstituted.

The term “heterocycloalkenyl,” as used herein, refers to aheterocycloalkyl group, as defined above, wherein the heterocycloalkylgroup contains from 4 to 10 ring atoms, and at least one endocycliccarbon-carbon or carbon-nitrogen double bond. A heterocycloalkenyl groupcan be joined via a ring carbon or ring nitrogen atom. In oneembodiment, a heterocycloalkenyl group has from 4 to 7 ring atoms. Inanother embodiment, a heterocycloalkenyl group is monocyclic and has 5or 6 ring atoms. In another embodiment, a heterocycloalkenyl group isbicyclic. A heterocycloalkenyl group can optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocycloalkenylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of heterocycloalkenyl groups include1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,fluoro-substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like and the like. A ringcarbon atom of a heterocycloalkenyl group may be functionalized as acarbonyl group. In one embodiment, a heterocycloalkenyl group is a5-membered heterocycloalkenyl. In another embodiment, aheterocycloalkenyl group is a 6-membered heterocycloalkenyl. The term “4to 7-membered heterocycloalkenyl” refers to a heterocycloalkenyl grouphaving from 4 to 7 ring atoms. Unless otherwise indicated, aheterocycloalkenyl group is unsubstituted.

The term “ring system substituent,” as used herein, refers to asubstituent group attached to an aromatic or non-aromatic ring systemwhich, for example, replaces an available hydrogen on the ring system.Ring system substituents may be the same or different, each beingindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl,-alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl,—OH, hydroxyalkyl, haloalkyl, —O-alkyl, —O-haloalkyl, -alkylene-O-alkyl,—O-aryl, —O— alkylene-aryl, acyl, —C(O)-aryl, halo, —NO₂, —CN, —SF₅,—C(O)OH, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-alkylene-aryl, —S(O)-alkyl,—S(O)₂-alkyl, —S(O)-aryl, —S(O)₂-aryl, —S(O)-heteroaryl,—S(O)₂-heteroaryl, —S-alkyl, —S-aryl, —S-heteroaryl, —S-alkylene-aryl,—S-alkylene-heteroaryl, —S(O)₂-alkylene-aryl,—S(O)₂-alkylene-heteroaryl, —Si(alkyl)₂, —Si(aryl)₂, —Si(heteroaryl)₂,—Si(alkyl)(aryl), —Si(alkyl)(cycloalkyl), —Si(alkyl)(heteroaryl),cycloalkyl, heterocycloalkyl, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),—N(Y₁)(Y₂), -alkylene-N(Y₁)(Y₂), —C(O)N(Y₁)(Y₂) and —S(O)₂N(Y₁)(Y₂),wherein Y₁ and Y₂ can be the same or different and are independentlyselected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl,and -alkylene-aryl. “Ring system substituent” may also mean a singlemoiety which simultaneously replaces two available hydrogens on twoadjacent carbon atoms (one H on each carbon) on a ring system. Examplesof such moiety are methylenedioxy, ethylenedioxy, —C(CH₃)₂— and the likewhich form moieties such as, for example:

The term “silylalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a —Si(R^(x))₃ group, wherein each occurrence ofIV is independently C₁-C₆ alkyl, phenyl or a 3- to 6-membered cycloalkylgroup. In one embodiment, a silylalkyl group has from 1 to 6 carbonatoms. In another embodiment, a silyl alkyl group contains a —Si(CH₃)₃moiety. Non-limiting examples of silylalkyl groups include —CH₂—Si(CH₃)₃and —CH₂CH₂—Si(CH₃)₃.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture.

The term “in substantially purified form,” as used herein, refers to thephysical state of a compound after the compound is isolated from asynthetic process (e.g., from a reaction mixture), a natural source, ora combination thereof. The term “in substantially purified form,” alsorefers to the physical state of a compound after the compound isobtained from a purification process or processes described herein orwell-known to the skilled artisan (e.g., chromatography,recrystallization and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell-known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any substituent or variable (e.g., alkyl, R⁵, etc.) occurs morethan one time in any constituent or in Formula (I), its definition oneach occurrence is independent of its definition at every otheroccurrence, unless otherwise indicated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g., a drugprecursor) that is transformed in vivo to provide a SubstitutedBenzofuran Compound or a pharmaceutically acceptable salt or solvate ofthe compound. The transformation may occur by various mechanisms (e.g.,by metabolic or chemical processes), such as, for example, throughhydrolysis in blood.

For example, if a Substituted Benzofuran Compound or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a Substituted Benzofuran Compound contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkyl, α-amino(C₁-C₄)alkylene-aryl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,—P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resultingfrom the removal of a hydroxyl group of the hemiacetal form of acarbohydrate), and the like.

If a Substituted Benzofuran Compound incorporates an amine functionalgroup, a prodrug can be formed by the replacement of a hydrogen atom inthe amine group with a group such as, for example, R-carbonyl-,RO-carbonyl-, NRR′-carbonyl-wherein R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, a natural α-aminoacyl,C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ whereinY² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl; carboxy (C₁-C₆)alkyl;amino(C₁-C₄)alkyl or mono-N- or di-N,N—(C₁-C₆)alkylaminoalkyl; —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di-N,N—(C₁-C₆)alkylaminomorpholino; piperidin-1-yl or pyrrolidin-1-yl, and the like.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy group of a hydroxyl compound, in which the non-carbonylmoiety of the carboxylic acid portion of the ester grouping is selectedfrom straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g.,methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example,phenoxymethyl), aryl (e.g., phenyl optionally substituted with, forexample, halogen, C₁₋₄alkyl, —O—(C₁₋₄alkyl) or amino); (2) sulfonateesters, such as alkyl- or aralkylsulfonyl (for example,methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl);(4) phosphonate esters and (5) mono-, di- or triphosphate esters. Thephosphate esters may be further esterified by, for example, a C₁₋₂₀alcohol or reactive derivative thereof, or by a 2,3-di(C₆₋₂₄)acylglycerol.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of solvates includeethanolates, methanolates, and the like. A “hydrate” is a solvatewherein the solvent molecule is water.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS Pharm Sci Techours., 5(1), article 12 (2004); and A. L. Binghamet al, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanroom temperature, and cooling the solution at a rate sufficient to formcrystals which are then isolated by standard methods. Analyticaltechniques such as, for example IR spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

The Substituted Benzofuran Compounds can form salts which are alsowithin the scope of this invention. Reference to a SubstitutedBenzofuran Compound herein is understood to include reference to saltsthereof, unless otherwise indicated. The term “salt(s)”, as employedherein, denotes acidic salts formed with inorganic and/or organic acids,as well as basic salts formed with inorganic and/or organic bases. Inaddition, when a Substituted Benzofuran Compound contains both a basicmoiety, such as, but not limited to a pyridine or imidazole, and anacidic moiety, such as, but not limited to a carboxylic acid,zwitterions (“inner salts”) may be formed and are included within theterm “salt(s)” as used herein. In one embodiment, the salt is apharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salt. In another embodiment, the salt is other than apharmaceutically acceptable salt. Salts of the Compounds of Formula (I)may be formed, for example, by reacting a Substituted BenzofuranCompound with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates(“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates,propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates) and the like.In one embodiment, a compound of formula (I) is present as itsdihydrochloride salt. In another embodiment, a compound of formula (I)is present as its dimesylate salt. Additionally, acids which aregenerally considered suitable for the formation of pharmaceuticallyuseful salts from basic pharmaceutical compounds are discussed, forexample, by P. Stahl et al, Camille G. (eds.) Handbook of PharmaceuticalSalts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Bergeet al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, ThePractice of Medicinal Chemistry (1996), Academic Press, New York; and inThe Orange Book (Food & Drug Administration, Washington, D.C. on theirwebsite). These disclosures are incorporated herein by referencethereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamine, t-butyl amine, choline, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well-known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Sterochemically pure compounds may also be prepared by using chiralstarting materials or by employing salt resolution techniques. Also,some of the Substituted Benzofuran Compounds may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be directly separated using chiral chromatographictechniques.

It is also possible that the Substituted Benzofuran Compounds may existin different tautomeric forms, and all such forms are embraced withinthe scope of the invention. For example, all keto-enol and imine-enamineforms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, hydrates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention. If a SubstitutedBenzofuran Compound incorporates a double bond or a fused ring, both thecis- and trans-forms, as well as mixtures, are embraced within the scopeof the invention.

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to apply equally to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

In the Compounds of Formula (I), the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of generic Formula I.For example, different isotopic forms of hydrogen (H) include protium(¹H) and deuterium (²H). Protium is the predominant hydrogen isotopefound in nature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched Compoundsof Formula (I) can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates. In one embodiment, a Compound of Formula (I) has one ormore of its hydrogen atoms replaced with deuterium.

Polymorphic forms of the Substituted Benzofuran Compounds, and of thesalts, solvates, hydrates, esters and prodrugs of the SubstitutedBenzofuran Compounds, are intended to be included in the presentinvention.

The following abbreviations are used below and have the followingmeanings: Ac is acyl; AcOH is acetic acid; BOC or Boc istert-butyloxycarbonyl; Boc₂O is Boc anhydride; dba isdibenzylideneacetone; DCM is dichloromethane; DMA isN,N-dimethylacetamide; DMF is N,N-dimethylformamide; dppf isdiphenylphosphinoferrocene; dppm is bis(diphenylphosphino)methane; EDCIis 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EtOAc is ethylacetate; Et₂O is diethyl ether; Et₃N is triethylamine; HOBT is 1-hydroxy1H-benzotriazole; HPLC is high performance liquid chromatography; HRMSis high resolution mass spectrometry; KOAc is potassium acetate; LCMS isliquid chromatography/mass spectrometry; MeOH is methanol; PdCl₂(dppf)₂is [1,1′-Bis(diphenylphosphino)ferrocene]dichloro palladium(II); PE ispetroleum ether; pinacol₂B₂ is bis(pinacolato)diboron; p-TsOH isp-toluenesulfonic acid; TFA is trifluoroacetic acid; THF istetrahydrofuran; and TLC is thin-layer chromatography.

The Compounds of Formula (I)

The present invention provides Substituted Benzofuran Compounds ofFormula

wherein U, V, W, X, Y¹, Y², Z, R² and R³ are as defined above for theCompounds of Formula (I).

In one embodiment, A is:

In another embodiment, A is:

In one embodiment, U is —N(R⁵)—.

In another embodiment, U is —C(R⁴)₂—.

In another embodiment, U is —CHR⁴—, wherein R⁴ is selected from H,pyridyl and phenyl, wherein said phenyl group can be optionallysubstituted with C₁-C₆ alkyl, C₁-C₆ haloalkyl or halo

In another embodiment, U is —N(R⁵)—.

In one embodiment, R¹ represents a single halo substituent.

In another embodiment, R¹ represents a single F substituent.

In one embodiment, R² is —C(O)NH—(C₁-C₆ alkyl).

In another embodiment, R² is —C(O)NH—CH₃.

In one embodiment, R³ is —N(R⁸)—S(O)_(n)—R⁹ and R⁸ and R⁹ are each C₁-C₆alkyl.

In another embodiment, R³ is —N(R⁸)—S(O)_(n)—R⁹ and R⁸ and R⁹ are eachmethyl.

In still another embodiment, U is —N(R⁵)— and R⁵ is selected from H;C₁-C₆ hydroxyalkyl; —C(O)O—(C₁-C₆ alkyl); 6-membered heteroaryl;6-membered heterocycloalkyl, which can be optionally substituted on aring carbon atom with one group selected from C₁-C₆ alkyl, halo—O—(C₁-C₆ alkyl) and C₁-C₆ haloalkyl, or optionally substituted on aring nitrogen atom with —C(O)O—(C₁-C₆ alkyl); phenyl, which can beoptionally substituted with one group selected from —O—(C₁-C₆ alkyl),halo, —CN, C₁-C₆ haloalkyl, —O—(C₁-C₆ haloalkyl) or —SO₂—(C₁-C₆ alkyl);and benzyl, which can be optionally substituted with halo or C₁-C₆haloalkyl.

In yet another embodiment, U is —N(R⁵)— and R⁵ is selected from H;2-hydroxyethyl; —C(O)O-t-butyl; pyridyl; tetrahydropyranyl; phenyl,which can be optionally substituted with methoxy, F, Cl, —CN, —CF₃,—OCF₃ or —SO₂CH₃; benzyl, which can be optionally substituted with F or—CF₃; and pyrrolidinyl, which can be optionally substituted on its ringnitrogen atom with —C(O)O-t-butyl.

In one embodiment, for the compounds of formula (I), A is:

In one embodiment, for the compounds of formula (I), R¹ is a single Fgroup; R² is —C(O)NHCH₃; R³ is —N(CH₃)SO₂CH₃; and each occurrence of R¹⁰is independently H or F.

In one embodiment, the compounds of formula (I) have the formula (Ia):

or a pharmaceutically acceptable salt thereof,wherein:

V is N or —C(R^(4a))—;

W is N or —C(R⁴)—;

X and Z are each independently N or —C(R¹⁰)—;

one of Y¹ and Y² is —N— or —CH—, and the other of Y¹ and Y² is a carbonatom and represents the point of attachment of the benzofuran moietydepicted in formula (I);

R⁴ is selected from H, 5 or 6-membered heteroaryl and phenyl, whereinsaid phenyl group can be optionally substituted with C₁-C₆ alkyl, C₁-C₆haloalkyl or halo;

R^(4a) is selected from H, methyl and phenyl, wherein said phenyl groupcan be optionally substituted as set forth for the Compounds of Formula(I);

R⁵ is selected from H; C₁-C₆ hydroxyalkyl; —C(O)O—(C₁-C₆ alkyl);6-membered heteroaryl; 6-membered heterocycloalkyl, which can beoptionally substituted on a ring carbon atom with one group selectedfrom C₁-C₆ alkyl, halo —O—(C₁-C₆ alkyl) and C₁-C₆ haloalkyl, oroptionally substituted on a ring nitrogen atom with —C(O)O—(C₁-C₆alkyl); phenyl, which can be optionally substituted with one groupselected from —O—(C₁-C₆ alkyl), halo, —CN, C₁-C₆ haloalkyl, —O—(C₁-C₆haloalkyl) or —SO₂—(C₁-C₆ alkyl); and benzyl, which can be optionallysubstituted with halo or C₁-C₆ haloalkyl;

R⁸ and R⁹ are each C₁-C₆ alkyl;

each occurrence of R¹⁰ is independently H or halo; and

n is 1 or 2.

In one embodiment, for the compounds of formula (Ia), the group:

has the structure:

In one embodiment, for the compounds of formula (Ia), In one embodiment,for the compounds of formula (I), R⁵ is selected from H; 2-hydroxyethyl;—C(O)O-t-butyl; pyridyl; tetrahydropyranyl; phenyl, which can beoptionally substituted with methoxy, F, Cl, —CN, —CF₃, —OCF₃ or —SO₂CH₃;benzyl, which can be optionally substituted with F or —CF₃; andpyrrolidinyl, which can be optionally substituted on its ring nitrogenatom with —C(O)O-t-butyl.

In one embodiment, R⁸ and R⁹ are each methyl.

In one embodiment, for the compounds of formula (I) or (Ia), V is —N—.

In another embodiment, for the compounds of formula (I) or (Ia), V is—C(R^(4a))—.

In another embodiment, for the compounds of formula (I) or (Ia), V is—C(R^(4a))— and R^(4a) is selected from H, methyl or cyclopropyl.

In one embodiment, for the compounds of formula (I) or (Ia), W is N.

In another embodiment, for the compounds of formula (I) or (Ia), W is—C(R^(4b))—.

In another embodiment, for the compounds of formula (I) or (Ia), W is—C(R^(4b))— and R^(4b) is pyridyl or phenyl, wherein said phenyl groupcan be optionally substituted with one group selected from F, Cl or—CF₃.

In one embodiment, for the compounds of formula (I) or (Ia), U is—N(R⁵)—, V is —C(R^(4a))— and W is —C(R^(4b))—.

In another embodiment, for the compounds of formula (I) or (Ia), U is—N(R⁵)—, V is —C(R^(4a))— and W is N.

In another embodiment, for the compounds of formula (I) or (Ia), U is—C(R⁴)₂—, V is N and W is N.

In one embodiment, for the compounds of formula (I) or (Ia), X is—C(R¹⁰)—.

In another embodiment, for the compounds of formula (I) or (Ia), X is—CH—.

In another embodiment, for the compounds of formula (I) or (Ia), X is N.

In one embodiment, for the compounds of formula (I) or (Ia), Z is—C(R¹⁰)—.

In another embodiment, for the compounds of formula (I) or (Ia), Z is—CH—.

In another embodiment, for the compounds of formula (I) or (Ia), Z is N.

In one embodiment, for the compounds of formula (I) or (Ia), Y¹ is —CH—.

In another embodiment, for the compounds of formula (I) or (Ia), Y¹ isN.

In another embodiment, for the compounds of formula (I) or (Ia), Y^(1′)is carbon and is the point of attachment of the benzofuran group.

In one embodiment, for the compounds of formula (I) or (Ia), Y² is —CH—.

In another embodiment, for the compounds of formula (I) or (Ia), Y^(2′)is carbon and is the point of attachment of the benzofuran group.

In one embodiment, for the compounds of formula (I) or (Ia), R¹ is F; R²is —C(O)NHCH₃; R³ is —N(CH₃)SO₂CH₃; R⁸ and R⁹ are each methyl; and eachoccurrence of R¹⁰ is independently H or F.

In one embodiment, for the compounds of formula (Ia), R⁸ and R⁹ are eachmethyl and the group:

In one embodiment, the compounds of formula (I) have the formula (Ib):

or a pharmaceutically acceptable salt thereof,wherein:

L is N or CH;

M is N or CH;

Q is —CH(R^(4b));

V is —N— or —C(R^(4a))—;

R⁴ is selected from H, 5 or 6-membered heteroaryl and phenyl, whereinsaid phenyl group can be optionally substituted with C₁-C₆ alkyl, C₁-C₆haloalkyl or halo;

R^(4a) is selected from H, methyl and phenyl;

R^(4b) is selected from H, and phenyl, wherein said phenyl group isoptionally substituted with halo;

R⁵ is selected from H; C₁-C₆ hydroxyalkyl; —C(O)O—(C₁-C₆ alkyl);6-membered heteroaryl; 6-membered heterocycloalkyl, which can beoptionally substituted on a ring carbon atom with one group selectedfrom C₁-C₆ alkyl, halo —O—(C₁-C₆ alkyl) and C₁-C₆ haloalkyl, oroptionally substituted on a ring nitrogen atom with —C(O)O—(C₁-C₆alkyl); phenyl, which can be optionally substituted with one groupselected from —O—(C₁-C₆ alkyl), halo, —CN, C₁-C₆ haloalkyl, —O—(C₁-C₆haloalkyl) or —SO₂—(C₁-C₆ alkyl); and benzyl, which can be optionallysubstituted with halo or C₁-C₆ haloalkyl;

R⁸ and R⁹ are each C₁-C₆ alkyl; and

each occurrence of R¹⁰ is independently H or halo.

In one embodiment, for the compounds of formula (Ib), R⁸ and R⁹ are eachmethyl.

In one embodiment, for the compounds of formula (Ib), L is —CH.

In one embodiment, for the compounds of formula (Ib), M is —CH.

In one embodiment, for the compounds of formula (Ib), Q is —CH-phenyl,wherein said phenyl group if optionally substituted with halo.

In another embodiment, for the compounds of formula (Ib), Q is—CH-(4-fluorophenyl).

In one embodiment, for the compounds of formula (Ib), V is N.

In another embodiment, for the compounds of formula (Ib), V is phenyl.

In one embodiment, for the compounds of formula (Ib), R⁸ and R⁹ are eachmethyl and the group:

In another embodiment of the invention, the compound of the invention isone of compounds 1-114, as depicted in the Examples below, or apharmaceutically acceptable salt thereof.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of acompound of formula (I) and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising a secondtherapeutic agent selected from the group consisting of HCV antiviralagents, immunomodulators, and anti-infective agents.

(c) The pharmaceutical composition of (b), wherein the HCV antiviralagent is an antiviral selected from the group consisting of directinhibitors of HCV, including but not limited to NS3 and NS3/4A proteaseinhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.

(d) A pharmaceutical combination that is (i) a compound of formula (I)and (ii) a second therapeutic agent selected from the group consistingof HCV antiviral agents, immunomodulators, and anti-infective agents;wherein the compound of formula (I) and the second therapeutic agent areeach employed in an amount that renders the combination effective forinhibiting HCV NS5B activity, or for inhibiting HCV viral replication,or for treating HCV infection and/or reducing the likelihood or severityof symptoms of HCV infection.

(e) The combination of (d), wherein the HCV antiviral agents are one ormore antiviral agents selected from the group consisting of directinhibitors of HCV, including but not limited to NS3 and NS3/4A proteaseinhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.

(f) A use of a compound of formula (I) in the preparation of amedicament for inhibiting HCV NS5B activity in a subject in need thereof

(g) A use of a compound of formula (I) in the preparation of amedicament for preventing and/or treating infection by HCV in a subjectin need thereof

(h) A method of treating HCV infection and/or reducing the likelihood orseverity of symptoms of HCV infection in a subject in need thereof,which comprises administering to the subject an effective amount of acompound of formula (I).

(i) The method of (h), wherein the compound of formula (I) isadministered in combination with an effective amount of at least onesecond therapeutic agent selected from the group consisting of HCVantiviral agents, immunomodulators, and anti-infective agents.

(j) The method of (i), wherein the HCV antiviral agent is an antiviralselected from the group consisting of direct inhibitors of HCV,including but not limited to NS3 and NS3/4A protease inhibitors, NS5Ainhibitors and HCV NS5B polymerase inhibitors.

(k) A method of inhibiting HCV viral replication and/or HCV viralproduction in a cell-based system, which comprises administering to thesubject an effective amount of a compound of formula (I) in combinationwith an effective amount of at least one second therapeutic agentselected from the group consisting of HCV antiviral agents,immunomodulators, and anti-infective agents.

(l) The method of (k), wherein the HCV antiviral agent is an antiviralselected from the group consisting of direct inhibitors of HCV,including but not limited to NS3 and NS3/4A protease inhibitors, NS5Ainhibitors and HCV NS5B polymerase inhibitors.

(m) A method of inhibiting HCV NS5B activity in a subject in needthereof, which comprises administering to the subject the pharmaceuticalcomposition of (a), (b), or (c) or the combination of (d) or (e).

(n) A method of treating HCV infection and/or reducing the likelihood orseverity of symptoms of HCV infection in a subject in need thereof,which comprises administering to the subject the pharmaceuticalcomposition of (a), (b), or (c) or the combination of (d) or (e).

The present invention also includes a compound of the present inventionfor use (i) in, (ii) as a medicament for, or (iii) in the preparation ofa medicament for: (a) inhibiting HCV NS5B activity, or (b) inhibitingHCV viral replication, or (c) treating HCV infection and/or reducing thelikelihood or severity of symptoms of HCV infection, or (d) use inmedicine. In these uses, the compounds of the present invention canoptionally be employed in combination with one or more secondtherapeutic agents selected from HCV antiviral agents, anti-infectiveagents, and immunomodulators.

In the embodiments of the compounds and salts provided above, it is tobe understood that each embodiment may be combined with one or moreother embodiments, to the extent that such a combination provides astable compound or salt and is consistent with the description of theembodiments. It is further to be understood that the embodiments ofcompositions and methods provided as (a) through (n) above areunderstood to include all embodiments of the compounds and/or salts,including such embodiments as result from combinations of embodiments.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations, uses and methods set forth in (a) through(n) above, wherein the compound of the present invention employedtherein is a compound of one of the embodiments, aspects, classes,sub-classes, or features of the compounds described above. In all ofthese embodiments, the compound may optionally be used in the form of apharmaceutically acceptable salt or hydrate as appropriate.

Methods for Making the Compounds of Formula (I)

The Compounds of Formula (I) may be prepared from known or readilyprepared starting materials, following methods known to one skilled inthe art of organic synthesis. Methods useful for making the Compounds ofFormula (I) are set forth in the Examples below and generalized inSchemes 1-5 below. Alternative synthetic pathways and analogousstructures will be apparent to those skilled in the art of organicsynthesis. All stereoisomers and tautomeric forms of the compounds arecontemplated.

Some commercially available starting materials and intermediates usedfor the synthesis of the Compounds of Formula (I) are available whichcontain intact fused polycyclic bicyclic ring systems. These startingmaterials and intermediates are available from commercial suppliers suchas Sigma-Aldrich (St. Louis, Mo.) and Acros Organics Co. (Fair Lawn,N.J.). Such starting materials and intermediates compounds are used asreceived.

Scheme 1 shows a method useful for making compounds of formula F, whichcorrespond to the Compounds of Formula (I), wherein R¹ is F; R² isC(O)NHCH₃; R³ is —N(CH₃)SO₂CH₃; U is —N(R⁵)—; V is —C(R^(4a))—; W is N;X and Z are each —CH—; and one of Y¹ and Y² is —CH— and the other of Y¹and Y² is the point of attachment of the benzofuran moiety.

Wherein R^(4a) and R⁵ are defined above for the Compounds of Formula(I).

Starting from compound A (X=Cl, Br or I,) which coupling with amines(R₁=Ar or Alk) afford compounds of formula B. Compounds f of formula Ccan be generated by reduction of the nitro group in compounds B, and theamino groups in compounds C is then cyclized with ortho esters orcarboxylic acids to furnish compounds D (R=H, Alk or Ar). Transitionmetal mediated coupling of compounds D with compound E provides thetarget compounds of general structure F.

Scheme 2 shows an alternate method useful for making compounds offormula F, which correspond to the Compounds of Formula (I), wherein R¹is F; R² is C(O)NHCH₃; R³ is —N(CH₃)SO₂CH₃; U is —N(R⁵)—; V is—C(R^(4a))—; W is N; X and Z are each —CH—; and one of Y¹ and Y² is —CH—and the other of Y¹ and Y² is the point of attachment of the benzofuranmoiety.

Compounds of formula D can be converted to corresponding boronic estersG by reacting with bis(pinacolato)diboron in the presence of a palladiumcatalyst. Compounds of formula G can then be coupled with a brominatedbenzofuran compound of formula H to provide compounds of formula F.

Scheme 3 shows a method useful for making compounds of formula K, whichcorrespond to the Compounds of Formula (I), wherein R¹ is F; R² isC(O)NHCH₃; R³ is —N(CH₃)SO₂CH₃; U is —N(R⁵)—; V is —C(R^(4a))—; W is—C(R⁴)—; X and Z are each —CH—; and one of Y¹ and Y² is —CH— and theother of Y¹ and Y² is the point of attachment of the benzofuran moiety.

Compounds of formula I (G=Cl, Br or I) can be converted to compounds offormula J (R⁵=alkyl, aryl or heteroaryl) in the presence of transitionmetal catalyst or alkylation condition. A compound of formula J can thenbe reacted with a compound of formula E to provide the compounds offormula K.

Scheme 4 shows a method useful for making compounds of formula P, whichcorrespond to the Compounds of Formula (I), wherein R¹ is F; R² isC(O)NHCH₃; R³ is pyrroldinone; U is —N(R⁵)—; V is —C(R^(4a))—; W is N; Xand Z are each —CH—; and one of Y¹ and Y² is —CH— and the other of Y¹and Y² is the point of attachment of the benzofuran moiety.

Compound L can be reacted with treated with 4-chlorobutanoyl chloride toprovide compound M. Base-catalyzed hydrolysis of M provides carboxylicacid compound N, which can be condensed with methanamine using commonamide forming reagents to provide compound O. Transition metal mediatedcoupling of compound O with compound G provides the compounds of formulaP.

Scheme 5 shows a method useful for making compound E, which is aintermediate useful for making the Compounds of Formula (I).

Intermediate boronic acid compound E can be made by reactingbromo-substituted benzofuran compound Q with bis(pinacolato)diboron inthe presence of an appropriate palladium catalyst.

One skilled in the art of organic synthesis will recognize that thesynthesis of compounds with multiple reactive functional groups, such as—OH and NH₂, may require protection of certain functional groups (i.e.,derivatization for the purpose of chemical compatibility with aparticular reaction condition). Suitable protecting groups for thevarious functional groups of these compounds and methods for theirinstallation and removal are well-known in the art of organic chemistry.A summary of many of these methods can be found in Greene & Wuts,Protecting Groups in Organic Synthesis, John Wiley & Sons, 3^(rd)edition (1999).

One skilled in the art of organic synthesis will also recognize that oneroute for the synthesis of the Compounds of Formula (I) may be moredesirable depending on the choice of appendage substituents.Additionally, one skilled in the relevant art will recognize that insome cases the order of reactions may differ from that presented hereinto avoid functional group incompatibilities and thus adjust thesynthetic route accordingly.

Compounds of formula E, F, K and P may be further elaborated usingmethods that would be well-known to those skilled in the art of organicsynthesis or, for example, the methods described in the Examples below,to make the full scope of the Compounds of Formula (I).

The starting materials used and the intermediates prepared using themethods set forth above in Schemes 1-5 may be isolated and purified ifdesired using conventional techniques, including but not limited tofiltration, distillation, crystallization, chromatography and alike.Such materials can be characterized using conventional means, includingphysical constants and spectral data.

EXAMPLES General Methods

The compounds described herein can be prepared according to theprocedures of the following schemes and examples, using appropriatematerials and are further exemplified by the following specificexamples. The compounds illustrated in the examples are not, however, tobe construed as forming the only genus that is considered as theinvention. The examples further illustrate details for the preparationof the compounds of the present invention. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thesecompounds. All temperatures are degrees Celsius unless otherwise noted.Mass spectra (MS) were measured by electrospray ion-mass spectroscopy(ESI). ¹H NMR spectra were recorded at 400-500 MHz. Compounds describedherein were synthesized as a racemic mixture unless otherwise stated inthe experimental procedures.

Example 1 Preparation of Compound 1

Step 1—Synthesis of 5-bromo-N-(4-methoxyphenyl)-2-nitroaniline

To a solution of 4-methoxyaniline (560 mg, 4.6 mmol) in anhydrous THF(10 mL) was added NaH (273 mg, 6.8 mmol) little by little at ice-bath,and then the mixture was allowed to stir at room temperature for 30minutes. After 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.6 mmol) in THFwas added dropwise, the mixture was allowed to stir at 30˜40° C.overnight. After the reaction mixture was quenched with water, themixture was extracted with EtOAc. The organic phase was dried withNa₂SO₄ and concentrated in vacuo. The resulting residue was purifiedusing column chromatography (eluted with PE:EtOAc=20:1) to provide5-bromo-N-(4-methoxyphenyl)-2-nitroaniline (1.0 g, yield: 68.2%). ¹H-NMR(CDCl₃, 400 MHz) δ 9.34 (s, 1H), 7.98˜8.00 (m, 1H), 7.26˜7.35 (m, 2H),6.73˜6.82 (m, 3H), 3.78 (s, 3H). (M+H)⁺: 323/325.

Step 2—Synthesis of 5-bromo-N¹-(4-methoxyphenyl)benzene-1,2-diamine

A mixture of 5-bromo-N-(4-methoxyphenyl)-2-nitroaniline (1.0 g, 3.1mmol), Fe (518 mg, 9.3 mmol) and NH₄Cl (993 mg, 18.6 mmol) inTHF:MeOH:H₂O (10 mL:10 mL:10 mL) was refluxed for 3 hours. After thereaction mixture was filtrated, the filtrate was concentrated, theresulting residue was purified using column chromatography eluted withPE:EtOAc=20:1 to provide 5-bromo-N¹-(4-methoxyphenyl)benzene-1,2-diamine(0.6 g, yield: 66.2%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.35 (s, 1H), 7.03 (s,1H), 6.90˜6.92 (m, 1H), 6.76˜6.80 (m, 3H), 6.57˜6.59 (m, 1H), 4.96 (s,1H), 3.72 (s, 3H), 4.96 (s, 2H). (M+H)⁺: 293/295.

Step 3—Synthesis of 6-bromo-1-(4-methoxyphenyl)-1H-benzo[d]imidazole

A mixture of 5-bromo-N⁴-(4-methoxyphenyl)benzene-1,2-diamine (300 mg,1.0 mmol) and p-TsOH (194 mg, 1.0 mmol) in CH(OCH₃)₃ (10 mL) wasrefluxed for 3 hours. After the reaction mixture was diluted with EtOAc,the mixture was washed with saturated NaHCO₃, dried (Na₂SO₄) andconcentrated in vacuo. The resulting residue was purified using columnchromatography (eluted with PE:EtOAc=12:1) to provide6-bromo-1-(4-methoxyphenyl)-1H-benzo[d]imidazole (180 g, yield: 58.1%).¹H-NMR (CDCl₃, 400 MHz) δ 8.03 (s, 1H), 7.6-37.65 (m, 2H), 7.32-7.36 (m,2H), 6.94-6.99 (m, 3H), 3.81 (s, 3H). (M+H)⁺: 303/305.

Step 4—Synthesis of2-(4-fluorophenyl)-5-(1-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of6-bromo-1-(4-methoxyphenyl)-1H-benzo[d]imidazole (85 mg, 0.28 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 100 mg, 0.20 mmol) in 1,4-dioxane (2 mL) was addedPd(dppf)Cl₂ (10 mg) and K₃PO₄ (85 mg, 0.4 mmol) under N₂. The mixturewas heated to 100° C. overnight. The reaction mixture was cooled to roomtemperature and filtered. The filtrate was washed with H₂O, brine, driedover Na₂SO₄. After being concentrated in vacuo, the resulting residuewas purified using prep-TLC to provide2-(4-fluorophenyl)-5-(1-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(45 mg, yield: 26.8%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.95 (s, 1H), 8.01 (d,J=8.0 Hz, 1H), 7.76˜7.85 (m, 4H), 7.49˜7.56 (m, 4H), 7.1˜37.17 (m, 2H),7.05 (d, J=8.0 Hz, 2H), 5.81 (s, 1H), 3.83 (s, 3H), 2.97 (s, 3H), 2.90(d, J=4.4 Hz, 3H), 2.82 (s, 3H). (M+H)⁺: 599.

Compounds 2-38, depicted in the table below, were prepared using themethod described above and substituting the appropriate reactants andreagents.

MS Compound Structure NMR (M + H)⁺  2

¹H-NMR (CDCl₃, 400 MHz) δ 9.19 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H),7.78~7.84 (m, 4H), 7.55~7.64 (m, 6H), 7.48 (s, 1H), 7.14 (t, J = 8.4 Hz,2H), 5.95~6.08 (br, 1H), 2.97 (s, 3H), 2.87 (d, J = 4.8 Hz, 3H), 2.85(s, 3H). 569  3

¹H-NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H),7.84~7.85 (m, 2H), 7.77 (s, 1H), 7.60~7.63 (m, 1H), 7.56 (s, 1H), 7.52(s, 1H), 7.45~7.47 (m, 2H), 7.31~7.36 (m, 2H), 7.12~7.16 (m, 2H), 5.74(d, J = 4.4 Hz, 1H), 3.01 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H), 2.94 (s,3H). 587  4

¹H-NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H),7.76~7.85 (m, 4H), 7.49~7.56 (m, 4H), 7.13~7.17 (m, 2H), 7.05 (d, J =8.0 Hz, 2H), 5.81 (s, 1H), 3.83 (s, 3H), 2.97 (s, 3H), 2.90 (d, J = 4.4Hz, 3H), 2.82 (s, 3H). 599  5

¹H-NMR (CDCl₃, 400 MHz) δ 8.54 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H),7.90~7.77 (m, 8H), 7.48 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.20~7.13 (m,2H), 5.75 (d, J = 5.2 Hz, 1H), 2.90~2.96 (m, 9H). 594  6

¹H-NMR (CDCl₃, 400 MHz) δ 8.68 (s, 1H), 8.04 (s, 1H), 7.99 (d, J = 8.4Hz, 1H), 7.96~7.73 (m, 7H), 7.52 (d, J = 10.0 Hz, 2H), 7.20 (t, J = 8.4Hz, 2H), 6.00 (s, 1H), 2.99~2.95 (m, 9H). 594  7

¹H-NMR (CDCl₃, 400 MHz) δ 8.49 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 7.2 Hz,1H), 7.81~7.88 (m, 6H), 7.75 (d, J = 8.0 Hz, 2H), 7.50 (s, 1H), 7.43 (d,J = 8.4 Hz, 1H), 7.15 (t, J = 8.8 Hz, 2H), 5.74 (s, 1H), 2.97 (s, 3H),2.90 (d, J = 4.8 Hz, 3H), 2.84 (s, 3H). 637  8

¹H-NMR (CDCl₃, 400 MHz) δ 8.14 (s, 1H), 7.90~7.86 (m, 3H), 7.81 (d, J =6.8 Hz, 1H), 7.77 (d, J = 6.0 Hz, 2H), 7.70~7.66 (m, 3H), 7.51 (d, J =4.0 Hz, 1H), 7.36 (d, J = 9.6 Hz, 1H), 7.16~7.11 (m, 2H), 5.75 (s, 1H),3.00 (s, 3H), 2.90 (d, J = 1.2 Hz, 3H), 2.70 (s, 3H). 637  9

¹H-NMR (CDCl₃, 400 MHz) δ 8.05 (s, 1H), 7.95~7.90 (m, 4H), 7.79 (s, 2H),7.69 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.38 (dd, J₁ = 1.2 Hz, J₂ = 1.6Hz, 1H), 7.23~7.17 (m, 3H), 5.82 (s, 1H), 3.04 (s, 3H), 2.96 (d, J = 5.2Hz, 3H), 2.49 (s, 3H). 637 10

¹H-NMR (CDCl₃, 400 MHz) δ 8.86 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H),7.84~7.90 (m, 4H), 7.53~7.63 (m, 6H), 7.17~7.22 (m, 2H), 5.86 (br s,1H), 2.92~2.99 (m, 9H). 603 11

¹H-NMR (CDCl₃, 400 MHz) δ 8.85 (s, 1H), 8.01 (s, 1H), 7.78~7.86 (m, 3H),7.64 (s, 2H), 7.52~7.54 (m, 5H), 7.14~7.18 (m, 2H), 6.03 (s, 1H), 3.01(s, 3H), 2.92 (d, J = 4.0 Hz, 3H), 2.73 (s, 3H). 603 12

¹H-NMR (CDCl₃, 400 MHz) δ 8.46 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H),7.85~7.88 (m, 2H), 7.79 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.48 (d, J= 8.0 Hz, 3H), 7.43 (d, J = 9.2 Hz, 2H), 7.15 (t, J = 8.4 Hz, 2H), 5.75(t, J = 4.0 Hz, 1H), 3.00 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H), 2.75 (s,3H). 603 13

¹H-NMR (CDCl₃, 400 MHz) δ 8.24 (s, 1H), 8.18 (d, J = 8.4 Hz, 2H),7.96-7.87 (m, 7H), 7.56 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.24~7.19 (m,2H), 5.82 (s, 1H), 3.12 (s, 3H), 3.04 (s, 3H), 2.96 (d, J = 4.8 Hz, 3H),2.90 (s, 3H). 647 14

¹H-NMR (CDCl₃, 400 MHz) δ 8.02 (s, 1H), 7.80~7.88 (m, 3H), 7.74 (s, 1H),7.59 (s, 1H), 7.46~7.50 (m, 3H), 7.30 (d, J = 1.2 Hz, 1H), 7.16~7.20 (m,2H), 7.09~7.14 (m, 2H), 6.09 (s, 1H), 2.94 (s, 3H), 2.90 (d, J = 4.0 Hz,3H), 2.66 (m, 3H). 587 15

¹H-NMR (CDCl₃, 400 MHz) δ 8.09 (s, 1H), 7.82~7.88 (m, 3H), 7.75 (s, 1H),7.67 (s, 1H), 7.45-7.50 (m, 2H), 7.31~7.35 (m, 2H), 7.26 (d, J = 8.0 Hz,1H), 7.07~7.14 (m, 3H), 5.94 (s, 1H), 2.99 (s, 3H), 2.89 (d, J = 4.0 Hz,3H), 2.66 (m, 3H). 587 16

¹H-NMR (Methanol-d4, 400 MHz) δ 9.40 (s, 1H), 9.10 (s, 1H), 8.81 (d, J =1.2 Hz, 1H), 8.39~8.42 (m, 1H), 7.95~7.98 (m, 4H), 7.88 (s, 1H),7.79~7.81 (m, 1H), 7.70~7.77 (m, 2H), 7.27~7.31 (m, 2H), 3.09 (s, 3H),3.06 (s, 3H), 2.93 (m, 3H). 570 17

¹H-NMR (CDCl₃, 400 MHz) δ 8.61 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H),7.83~7.87 (m, 2H), 7.78-7.82 (m, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.49 (s,1H), 7.46 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.15 (t, J =8.4 Hz, 2H), 5.74 (d, J = 7.2 Hz, 1H), 2.96 (s, 3H), 2.90 (d, J = 4.8Hz, 3H), 2.84 (s, 3H). 653 18

¹H-NMR (CDCl₃, 400 MHz) δ 7.84~7.88 (m, 2H), 7.70 (t, J = 3.2 Hz, 2H),7.49~7.53 (m, 3H), 7.43 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.2 Hz, 2H),7.23 (d, J = 1.6 Hz, 1H), 7.13 (s, 1H), 7.09 (t, J = 6.8 Hz, 1H), 5.87(s, 1H), 2.98 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H), 2.50 (s, 3H), 2.48 (s,3H). 583 19

¹H-NMR (CDCl₃, 400 MHz) δ 7.85~7.88 (m, 2H), 7.72 (s, 1H), 7.70 (s, 1H),7.50 (s, 1H), 7.33~7.36 (m, 2H), 7.22~7.25 (m, 4H), 7.13 (t, J = 8.8 Hz,2H), 5.77 (s, 1H), 2.96 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H), 2.58 (s, 3H),2.47 (s, 3H). 601 20

¹H-NMR (CDCl₃, 400 MHz) δ 8.29 (s, 1H), 7.85 (t, J = 8.8 Hz, 2H), 7.78(s, 1H), 7.51~7.54 (m, 5H), 7.49 (s, 1H), 7.44~7.46 (m, 1H), 7.09~7.16(m, 3H), 5.74 (s, 1H), 3.02 (s, 3H), 2.91 (d, J = 4.8 Hz, 3H), 2.75 (s,3H). 587 21

¹H-NMR (400 MHz, CDCl₃) δ 9.05 (s, 1H), 8.12 (s, 1H), 7.95-7.99 (m, 2H),7.87 (s, 1H), 7.77-7.79 (m, 1H), 7.69~7.73 (m, 4H), 7.61-7.62 (m, 3H),7.20~7.24 (m, 2H), 6.01~6.02 (br, 1H), 3.19 (s, 3H), 3.01-3.02 (d, J =4.0 Hz, 3H), 2.85 (s, 3H). 569 22

¹H-NMR (CDCl₃, 400 MHz) δ 8.99 (s, 1H), 8.89 (d, J = 4.0 Hz, 1H), 8.79(s, 1H), 8.06 (s, 2H), 7.94~7.97 (m, 2H), 7.87 (s, 1H), 7.72 (s, 1H),7.70 (s, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.20~7.24 (m, 2H), 5.99 (s,1H), 3.18 (s, 3H), 3.01 (d, J = 4.0 Hz, 3H), 2.81 (s, 3H). 570 23

¹H-NMR (CDCl₃, 400 MHz) δ 7.98 (s, 1H), 7.86~7.90 (m, 2H), 7.78~7.82 (m,2H), 7.65 (s, 1H), 7.51 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.12~7.19 (m,2H), 5.84 (s, 1H), 4.31~4.38 (m, 3H), 2.87~2.94 (m, 8H), 2.68 (s, 3H),2.16~2.19 (m, 2H), 1.90~1.93 (m, 2H), 1.42 (s, 9H). 676 24

¹H-NMR (CDCl₃, 400 MHz) δ 9.08 (s, 1H), 7.96 (s, 2H), 7.85~7.89 (m, 3H),7.56 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.14~7.17 (m, 2H), 5.84 (br s,1H), 4.51 (s, 1H), 4.32 (s, 1H), 3.88~3.90 (m, 1H), 3.37 (s, 1H),3.02~3.04 (m, 1H), 2.86~2.95 (m, 9H), 2.32~2.35 (m, 1H), 2.15~2.17 (m,1H), 1.69~1.82 (m, 1H), 1.67~1.68 (m, 1H), 1.36 (s, 9H). 676 25

¹H-NMR (CDCl₃, 400 MHz) δ 8.00 (s, 1H), 7.86~7.89 (m, 2H), 7.70~7.75 (m,3H), 7.44 (s, 1H), 7.23~7.25 (m, 1H), 7.11 (t, J = 8.4 Hz, 2H), 6.40 (s,1H), 4.50~4.53 (m, 1H), 3.49~3.51 (m, 1H), 3.12~3.15 (m, 2H), 2.96~3.01(m, 1H), 2.92 (s, 3H), 2.87 (d, J = 4.8 Hz, 3H), 2.70~2.75 (m, 1H), 2.59(s, 3H), 2.20~2.23 (m, 1H), 2.00~2.10 (m, 1H), 1.77~1.89 (m, 2H). 576 26

¹H-NMR (CDCl₃, 400 MHz) δ 8.95 (s, 1H), 8.05 (s, 1H), 7.88~7.96 (m, 4H),7.54~7.55 (m, 2H), 7.18~7.24 (m, 2H), 5.97 (br s, 1H), 4.68~4.69 (m,1H), 4.16~4.19 (m, 2H), 3.59~3.64 (m, 2H), 2.93~2.96 (m, 9H), 2.15~2.27(m, 4H). 577 27

¹H-NMR (CDCl₃, 400 MHz) δ 9.14 (s, 1H), 7.94 (s, 1H), 7.85~7.90 (m, 4H),7.53 (d, J = 8.0 Hz, 1H), 7.14~7.16 (m, 3H), 5.92 (s, 1H), 4.46 (s, 2H),4.02 (s, 2H), 2.90~2.91 (m, 9H). 537 28

¹H-NMR (CDCl₃, 400 MHz) δ 8.07 (s, 1H), 7.90~7.94 (m, 2H), 7.83 (s, 1H),7.53~7.56 (m, 3H), 7.46 (s, 1H), 7.23~7.27 (m, 2H), 7.19 (t, J = 8.4 Hz,2H), 7.09 (d, J = 10.6 Hz, 1H), 5.91 (d, J = 4.8 Hz, 1H), 3.03 (s, 3H),2.96 (d, J = 4.8 Hz, 3H), 2.84 (s, 3H). 605 29

¹H-NMR (CDCl₃, 400 MHz) δ 7.88~7.93 (m, 3H), 7.78 (s, 1H), 7.48 (s, 1H),7.42 (s, 1H), 7.36~7.40 (m, 1H), 7.27~7.31 (m, 2H), 7.14 (t, J = 8.4 Hz,2H), 7.02 (d, J = 10.8 Hz, 1H), 6.21 (s, 1H), 2.93 (s, 3H), 2.92 (s,3H), 2.89 (s, 3H). 623 30

¹H-NMR (CDCl₃, 400 MHz) δ 8.10 (s, 1H), 7.90-7.93 (m, 2H), 7.84 (s, 1H),7.55 (d, J = 10.0 Hz, 2H), 7.17~7.21 (m, 4H), 7.13 (d, J = 10.8 Hz, 1H),6.89-6.93 (m, 1H), 5.90 (d, J = 3.6 Hz, 1H), 3.05 (s, 3H), 2.96 (d, J =4.8 Hz, 3H), 2.88 (s, 3H). 623 31

¹H-NMR (CDCl₃, 400 MHz) δ 8.11 (s, 1H), 7.84-7.87 (m, 2H), 7.81 (s, 1H),7.55 (s, 1H), 7.48 (s, 1H), 7.29 (t, J = 6.8 Hz, 2H), 7.10-7.15 (m, 3H),5.76 (d, J = 4.8 Hz, 1H), 2.97 (s, 3H), 2.91 (d, J = 3.6 Hz, 3H), 2.91(s, 3H). 641 32

¹H-NMR (CDCl₃, 400 MHz) δ 8.05~8.08 (m, 3H), 7.69 (s, 2H), 7.53 (s, 1H),7.40 (s, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 8.4 Hz, 2H), 6.95(s, 1H), 6.87 (d, J = 10.8 Hz, 1H), 3.11 (s, 3H), 3.07 (d, J = 4.4 Hz,3H), 2.75 (s, 3H), 1.92 (s, 3H). 644 33

¹H-NMR (CDCl₃, 400 MHz) δ 7.80~7.83 (m, 2H), 7.69 (s, 1H), 7.44 (s, 3H),7.30 (t, J = 8.0 Hz, 2H), 7.15 (t, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.96(s, 1H), 5.84 (s, 1H), 3.99 (s, 3H), 2.94 (s, 3H), 2.90 (d, J = 4.4 Hz,3H), 2.85 (s, 3H), 2.72 (s, 3H). 631 34

¹H-NMR (CDCl₃, 400 MHz) δ 7.91~7.91 (m, 2H), 7.75 (s, 1H), 7.45 (s, 1H),7.12 (t, J = 8.4 Hz, 2H), 7.07 (s, 1H), 6.86-6.97 (m, 4H), 6.96 (s, 1H),2.96 (d, J = 4.8 Hz, 3H), 2.92 (s, 3H), 2.84 (s, 3H), 2.30 (s, 3H). 63735

¹H-NMR (CDCl₃, 400 MHz) δ 9.10 (s, 1H), 8.86 (d, J = 4.0 Hz, 1H), 8.45(d, J = 2.4 Hz, 1H), 8.28 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.88~7.93(m, 2H), 7.82 (t, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.53 (d,J = 7.6 Hz, 1H), 7.20 (t, J = 8.4 Hz, 2H), 5.81 (s, 1H), 3.02 (s, 3H),2.96 (d, J = 4.8 Hz, 3H), 2.90 (s, 3H). 588 36

¹H-NMR (CDCl₃, 400 MHz) δ 8.77 (s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 8.51(s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.89~7.92 (m, 3H), 7.86 (s, 2H), 7.52(s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 8.8 Hz, 2H), 5.80 (d, J= 4.0 Hz, 1H), 2.99 (s, 3H), 2.95 (d, J = 4.8 Hz, 3H), 2.93 (s, 3H). 58837

¹H-NMR (CDCl₃, 400 MHz) δ 7.86~7.89 (m, 3H), 7.16 (s, 1H), 7.47 (s, 1H),7.13 (t, J = 8.4 Hz, 2H), 6.88~6.95 (m, 2H), 6.83 (d, J = 7.2 Hz, 2H),5.83 (s, 1H), 4.00 (s, 3H), 2.93 (s, 3H), 2.91 (d, J = 4.8 Hz, 3H), 2.76(s, 3H), 2.49 (s, 3H). 649 38

¹H NMR (CDCl₃, 400 MHz) δ 8.07 (s, 1H), 8.01~8.05 (m, 2H), 7.90 (s, 1H),7.69 (s, 1H), 7.54~7.62 (m, 5H), 7.49 (t, J = 7.2 Hz, 1H), 7.40~7.42 (m,2H), 7.14~7.19 (m, 2H), 6.58 (br s, 1H), 3.19 (s, 3H), 2.93 (d, J = 4.8Hz, 3H), 2.51 (s, 3H). 569

Example 2 Preparation of Compound 39

Step 1—Synthesis of2-chloro-5-nitro-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine

A mixture of 2,4-dichloro-5-nitropyrimidine (3.0 g, 15.5 mmol) inanhydrous THF (5 mL) was added dropwise 4-fluoroaniline (2.7 g, 15.5mmol) in THF at ice-bath, then the mixture was allowed to stir at roomtemperature for overnight. After the reaction mixture was concentrated,the resulting residue was purified using column chromatography elutedwith PE:EtOAc=40:1 to provide2-chloro-5-nitro-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine (3.6 g,yield: 69.0%). ¹H-NMR (CDCl₃, 400 MHz) δ 9.58 (s, 1H), 9.09 (s, 1H),7.50 (s, 2H), 7.0˜7.09 (m, 2H). MS (M+H)⁺: 345.

Step 2—Synthesis of2-chloro-N⁴-(4-(trifluoromethoxy)phenyl)pyrimidine-4,5-diamine

A mixture of2-chloro-5-nitro-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine (5.0 g,14.9 mmol), Fe (2.5 g, 44.8 mmol) and NH₄Cl (4.8 g, 89.6 mmol) inTHF:MeOH:H₂O (20 mL:20 mL:20 mL) was refluxed for 3 hours. After thereaction mixture was filtrated, the filtrate was concentrated, theresulting residue was purified using column chromatography eluted withPE:EtOAc=4:1 to provide2-chloro-N⁴-(4-(trifluoromethoxy)phenyl)pyrimidine-4,5-diamine (3.8 g,yield: 70.2%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.70 (s, 1H), 7.55-7.57 (m,2H), 7.1-97.21 (m, 1H), 7.12-7.14 (m, 2H). MS (M+H)⁺: 305.

Step 3—Synthesis of 2-chloro-9-(4-(trifluoromethoxy)phenyl)-9H-purine

A mixture of2-chloro-N⁴-(4-(trifluoromethoxy)phenyl)pyrimidine-4,5-diamine (1.0 g,3.3 mmol) in HCOOH (10 mL) was refluxed for 3 hours. After the reactionmixture was diluted with EtOAc, the mixture was washed with saturatedNaHCO₃, dried (Na₂SO₄), concentrated, the resulting residue was purifiedusing column chromatography eluted with PE:EtOAc=4:1 to provide2-chloro-9-(4-(trifluoromethoxy)phenyl)-9H-purine (460 mg, yield:44.5%). ¹H-NMR (CDCl₃, 400 MHz) δ 9.03 (s, 1H), 8.29 (s, 1H), 7.70˜7.72(m, 2H), 7.39˜7.42 (m, 2H). MS (M+H)⁺: 315.

Step 4—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(9-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)benzofuran-3-carboxamide

2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(9-(4-(trifluoromethoxy)phenyl)-9H-purin-2-yl)benzofuran-3-carboxamidewas prepared using the method described in Example 1. ¹H-NMR (CDCl₃, 400MHz) δ 9.46 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.00˜8.04 (m, 2H),7.85˜7.87 (m, 2H), 7.65 (s, 1H), 7.45˜7.47 (m, 2H), 7.17˜7.22 (m, 2H),6.27 (s, 1H), 3.34 (s, 3H), 3.02 (d, J=4.4 Hz, 3H), 2.82 (s, 3H). MS(M+H)⁺: 655.

Compounds 40-46, depicted in the table below, prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 40

¹H-NMR (CDCl₃, 400 MHz) δ 9.37 (s, 1H), 8.99 (s, 1H), 8.58 (d, J = 4.4Hz, 1H), 8.10 (s, 1H), 7.94-8.02 (m, 5H), 7.98~8.02 (m, 2H), 7.94~7.96(m, 2H), 3.30 (s, 3H), 2.86 (d, J = 4.4 Hz, 3H), 2.80 (s, 3H). 589 41

¹H-NMR (CDCl₃, 400 MHz) δ 9.46 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H),8.00~8.04 (m, 2H), 7.85~7.87 (m, 2H), 7.65 (s, 1H), 7.45~7.47 (m, 2H),7.17~7.22 (m, 2H), 6.27 (s, 1H), 3.34 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H),2.82 (s, 3H). 639 42

¹H-NMR (CDCl₃, 400 MHz) δ 9.30 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 8.01(d, J = 8.4 Hz, 2H), 7.91~7.94 (m, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.59(s, 1H), 7.14 (t, J = 8.4 Hz, 2H), 5.93 (brs, 1H), 3.30 (s, 3H), 2.94(d, J = 4.8 Hz, 3H), 2.79 (s, 3H). 596 43

¹H-NMR (CDCl₃, 400 MHz) δ 8.35 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.00(s, 1H), 7.89~7.92 (m, 2H), 7.61 (s, 1H), 7.59 (s, 1H), 7.47 (d, J = 5.2Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 6.81 (t, J = 8.4 Hz, 1H), 5.80 (s,1H), 3.22 (s, 3H), 2.94 (d, J = 4.8 Hz, 3H), 2.63 (s, 3H). 606 44

¹H-NMR (CDCl₃, 400 MHz) 8.30 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.01 (s,1H), 7.91-7.94 (dd, J = 8.8 Hz, 2H), 7.71~7.74 (m, 2H), 7.65 (s, 1H),7.59 (d, J = 8.4 Hz, 1H), 7.17~7.25 (m, 4H), 5.97 (brs, 1H), 3.12 (s,3H), 2.96 (d, J = 4.8 Hz, 3H), 2.60 (s, 3H). 588 45

¹H-NMR (DMSO-d6, 400 MHz) δ 9.18 (s, 1H), 8.16 (s, 1H), 7.99 (s, 1H),7.91~7.94 (m, 3H), 7.53 (s, 1H), 7.16 (d, J = 4.4 Hz, 2H), 7.11 (d, J =8.8 Hz, 2H), 6.88~6.92 (t, J = 8.8 Hz, 1H), 5.94 (d, J = 2.8 Hz, 1H),3.06 (s, 3H), 2.92 (d, J = 5.2 Hz, 3H), 2.90 (s, 3H). 606 46

¹H-NMR (CDCl₃, 400 MHz) 9.21 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H),7.94~7.97 (m, 2H), 7.86 (s, 1H), 7.55~7.59 (m, 3H), 7.26~7.30 (t, J =8.8 Hz, 2H), 7.15~7.19 (t, J = 8.4 Hz, 2H), 5.94 (brs, 1H), 3.07 (s,3H), 2.95~2.96 (t, J = 4.8 Hz, 3H), 2.91 (s, 3H). 588

Example 3 Preparation of Compound 47

Step 1—Synthesis of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate

Sodium hydride (2.4 g, 95 mmol) was dissolved in DMF (6 mL) to thisslowly added diethyl malonate (1.3 g, 79 mmol) under an inertatmosphere, once the addition was complete the reaction was allowed tostir for 10 minutes, 5-bromo-2-chloro-3-nitropyridine (1.0 g, 42 mmol)in DMF (2 mL) was slowly added to the anion, the reaction was maintainedat approximately 40° C. for 3 hours before being quenched with waster(10 mL), extracted with EtOAc, dried (Na₂SO₄) and concentrated, theresulting residue was purified using column chromatography eluted withPE:EtOAc=40:1 to provide diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate(1.0 g, yield: 67.8%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.86 (s, 1H), 8.60 (s,1H), 5.44 (s, 1H), 4.25˜4.30 (m, 4H), 1.25˜1.29 (m, 6H). (M+H)⁺:361/363.

Step 2—Synthesis of 5-bromo-2-methyl-3-nitropyridine

A mixture of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (1.2 g, 3.3mmol) was added to 7.0 N HCl (10 mL) and heated to refluxed for 5 hours,the reaction was cooled to room temperature and extracted withDCM:MeOH=10:1, the organic phase was dried (Na₂SO₄) and concentrated,the resulting residue was purified using column chromatography elutedwith PE:EtOAc=4:1 to provide 5-bromo-2-methyl-3-nitropyridine (0.7 g,yield: 89.7%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.76 (s, 1H), 8.40 (s, 1H),2.80 (s, 3H). (M+H)⁺: 217/219.

Step 3—Synthesis of2-(5-bromo-3-nitropyridin-2-yl)-N,N-dimethylethenamine

5-bromo-2-methyl-3-nitropyridine (1.0, 4.6 mmol) was dissolved in 10 mLof dry DMF and stirred under N₂, DMF-DMA (6.3 mL) was added dropwise.The reaction was heated to 90° C., after 15 min of heating a deepreddish color began to appear, and it was allowed to react for 4 hours,the solvent was removed by evaporation, the resulting residue waspurified using column chromatography eluted with PE:EtOAc=30:1 toprovide 2-(5-bromo-3-nitropyridin-2-yl)-N,N-dimethylethenamine (1.2 g,yield: 95.2%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.35 (s, 1H), 8.27 (s, 1H),7.99˜8.03 (m, 1H), 6.08˜6.11 (m, 1H), 2.98 (s, 6H). (M+H)⁺: 272/274.

Step 4—Synthesis of 6-bromo-1H-pyrrolo[3,2-b]pyridine

A mixture of 2-(5-bromo-3-nitropyridin-2-yl)-N,N-dimethylethenamine (1.0g, 3.7 mmol) and Fe (1.8 g, 32.2 mmol) in AcOH (10 mL) was heated at100° C. overnight. After the reaction mixture was filtrated, thefiltrate was concentrated, the resulting residue was purified usingcolumn chromatography eluted with PE:EtOAc=5:1 to provide6-bromo-1H-pyrrolo[3,2-b]pyridine (24 mg, yield: 33.3%). (M+H)⁺:197/199.

Step 5—Synthesis of 6-bromo-1-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridine

To a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.51 mmol),1-fluoro-4-iodobenzene (225 mg, 1.02 mmol) and Cs₂CO₃ (496 mg, 1.52mmol) in dioxane (2 mL) was allowed to stir at room temperature, the CuI(cat) and (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (cat) were addedunder N₂, and then the mixture was allowed to stir at reflux forovernight. After the reaction mixture was cooled to room temperature andfiltrated, the filtrate was concentrated, the resulting residue waspurified using prep-TLC (PE:EtOAc=1:1) to provide6-bromo-1-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridine (80 mg, yield:50.2%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.54 (s, 1H), 7.65 (s, 1H), 7.90˜7.94(m, 3H), 7.78˜7.80 (m, 1H), 7.6˜57.67 (m, 1H), 7.54˜7.57 (m, 1H).(M+H)⁺: 291/293.

Step 5—Synthesis of2-(4-fluorophenyl)-5-(1-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

The procedure of2-(4-fluorophenyl)-5-(1-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamidewas similar to that of Example 1. ¹H-NMR (CDCl₃, 400 MHz) δ 8.84 (s,1H), 8.55 (s, 1H), 7.9˜07.94 (m, 3H), 7.85˜7.86 (m, 1H), 7.54˜7.57 (m,3H), 7.26˜7.31 (m, 3H), 7.16˜7.21 (m, 2H), 5.99˜6.00 (br, 1H), 3.13 (s,3H), 2.98 (d, J=4.2 Hz, 3H), 2.96 (s, 3H). (M+H)⁺: 587.

Compounds 48-66, depicted in the table below, prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 48

¹H-NMR (CDCl₃, 400 MHz) δ 8.74 (s, 1H), 8.59 (s, 1H), 7.82~7.85 (m, 7H),7.69~7.71 (m, 2H), 7.49 (s, 1H), 7.11~7.16 (m, 2H), 6.22 (d, J = 3.2 Hz,1H), 3.05 (s, 3H), 2.89 (d, J = 4.4 Hz, 3H), 2.83 (s, 3H). 637 49

¹H-NMR (CDCl₃, 400 MHz) δ 8.86 (s, 1H), 8.70 (s, 1H), 7.92~8.02 (m, 6H),7.81 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.22~7.38 (m, 3H), 6.07 (s, 1H),3.14 (s, 3H), 3.10 (s, 3H), 3.01 (d, J = 4.8 Hz, 3H). 594 50

¹H-NMR (CDCl₃, 400 MHz) δ 8.85 (s, 1H), 8.58 (s, 1H), 7.95~8.02 (m, 3H),7.88 (d, J = 3.6 Hz, 1H), 7.55~7.65 (m, 5H), 7.22~7.33 (m, 3H), 6.07 (s,1H), 3.14 (s, 3H), 3.10 (s, 3H), 3.01 (d, J = 4.8 Hz, 3H). 603 51

¹H NMR (CDCl₃, 400 MHz) δ 8.85 (d, J = 7.2 Hz, 2H), 8.22 (s, 1H), 8.13(d, J = 7.2 Hz, 2H), 7.90~7.94 (m, 2H), 7.88 (s, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.54 (s, 1H), 7.53 (d, J = 3.2 Hz, 1H), 7.37 (d, J = 8.0 Hz,1H), 7.20~7.25 (m, 2H), 6.96 (d, J = 3.2 Hz, 1H), 5.85 (br s, 1H), 3.13(s, 3H), 2.99 (s, 3H), 2.97 (d, J = 4.8 Hz, 3H). 569 52

¹H NMR (CDCl₃, 400 MHz) δ 9.07 (s, 1H), 8.64 (d, J = 4.8 Hz, 1H), 8.55(d, J = 8.4 Hz, 1H), 7.90~7.95 (m, 2H), 7.80~7.86 (m, 3H), 7.76 (d, J =8.0 Hz, 1H), 7.53 (s, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.28-7.31 (m, 1H),7.16~7.21 (m, 2H), 6.85 (d, J = 3.2 Hz, 1H), 6.10 (br s, 1H), 2.99 (s,3H), 2.95 (d, J = 4.8 Hz, 3H), 2.92 (s, 3H). 569 53

¹H-NMR (CDCl₃, 400 MHz) δ 7.95~7.99 (m, 2H), 7.81 (s, 1H), 7.73 (d, J =0.8 Hz, 1H), 7.62~7.65 (m, 2H), 7.54~7.56 (m, 4H), 7.38~7.42 (m, 2H),7.29~7.33 (m, 1H), 7.17~7.22 (m, 2H), 6.73 (d, J = 3.2 Hz, 1H), 5.95 (brs, 1H), 3.15 (s, 3H), 2.99 (d, J = 4.8 Hz, 3H), 2.56 (s, 3H). 568 54

¹H-NMR (CDCl₃, 400 MHz) δ 7.95~7.99 (m, 2H), 7.81 (s, 1H), 7.72 (d, J =0.8 Hz, 1H), 7.61 (s, 1H), 7.47~7.52 (m, 3H), 7.23~7.33 (m, 2H),7.16~7.20 (m, 4H), 6.70 (d, J = 0.8 Hz, 1H), 5.83 (d, J = 4.0 Hz, 1H),3.12 (s, 3H), 2.97 (d, J = 4.0 Hz, 3H), 2.57 (s, 3H). 586 55

¹H-NMR (CDCl₃, 400 MHz) δ 7.95~7.99 (m, 2H), 7.67 (s, 1H), 7.59 (d, J =8.0 Hz, 1H), 7.56~7.58 (m, 2H), 7.42~7.47 (m, 1H), 7.32 (d, J = 4.0 Hz,1H), 7.28~7.30 (m, 2H), 7.20 (d, J = 2.0 Hz, 1H), 7.11~7.15 (m, 2H),7.00~7.05 (m, 1H), 6.66 (d, J = 4.0 Hz, 1H), 5.78 (d, J = 4.0 Hz, 1H),3.08 (s, 3H), 2.92 (d, J = 8.0 Hz, 3H), 2.51 (s, 3H). 586 56

¹H-NMR (CDCl₃, 400 MHz) δ 7.99~7.91 (m, 2H), 7.73~7.88 (m, 3H), 7.68 (s,1H), 7.58~7.62 (m, 3H), 7.54 (s, 1H), 7.34 (d, J = 4.0 Hz, 1H), 7.30 (d,J = 1.2 Hz, 1H), 7.10~7.18 (m, 2H), 6.70 (d, J = 4.0 Hz, 1H), 5.83 (d, J= 4.0 Hz, 1H), 3.06 (s, 3H), 2.90 (d, J = 8.0 Hz, 3H), 2.53 (s, 3H). 63657

¹H-NMR (CDCl₃, 400 MHz) δ 8.90 (s, 1H), 8.62 (s, 1H), 7.95~7.97 (m, 2H),7.88~7.91 (m, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.58~7.62 (m, 2H),7.50~7.58 (m, 1H), 7.34~7.49 (m, 2H), 7.17~7.21 (m, 2H), 6.78 (d, J =2.8 Hz, 1H), 5.90 (d, J = 4.0 Hz, 1H), 3.13 (s, 3H), 2.97 (d, J = 4.8Hz, 3H), 2.60 (s, 3H). 569 58

¹H-NMR (CDCl₃, 400 MHz) δ 8.80 (d, J = 4.0 Hz. 2H), 7.82~7.89 (m, 5H),7.80 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.43~7.46 (m, 2H),7.13~7.17 (m, 2H), 6.87 (d, J = 3.2 Hz, 1H), 5.78 (t, J = 0.8 Hz, 1H),3.07 (s, 3H), 2.91 (d, J = 4.2 Hz, 3H), 2.68 (s, 3H). 569 59

¹H-NMR (CDCl₃, 400 MHz) δ 7.93~7.98 (m, 2H), 7.78 (s, 1H), 7.73 (d, J =8.0 Hz, 1H), 7.58~7.62 (m, 2H), 7.50~7.54 (m, 2H), 7.35 (d, J = 3.2 Hz,1H), 7.16~7.24 (m, 5H), 6.72 (d, J = 2.8 Hz, 1H), 5.85 (br s, 1H), 3.07(s, 3H), 2.95 (d, J = 4.8 Hz, 3H), 2.62 (s, 3H). 586 60

¹H-NMR (CDCl₃, 400 MHz) δ 7.93~7.97 (m, 2H), 7.78 (s, 1H), 7.70~7.74 (m,2H), 7.58 (s, 1H), 7.45~7.51 (m, 1H), 7.37~7.39 (m, 2H), 7.16~7.28 (m,4H), 7.02~7.07 (m, 1H), 6.73 (d, J = 3.2 Hz, 1H), 5.88 (br s, 1H), 3.10(s, 3H), 2.95 (d, J = 4.8 Hz, 3H), 2.60 (s, 3H). 586 61

¹H-NMR (CDCl₃, 400 MHz) δ 7.93~7.97 (m, 2H), 7.70~7.80 (m, 7H), 7.58 (s,1H), 7.42 (d, J = 3.2 Hz, 1H), 7.17~7.27 (m, 3H), 6.77 (d, J = 3.2 Hz,1H), 5.84 (br s, 1H), 3.08 (s, 3H), 2.95 (d, J = 4.8 Hz, 3H), 2.70 (s,3H). 636 62

¹H-NMR (CDCl₃, 400 MHz) δ 8.71 (br s, 1H), 7.89~7.93 (m, 2H), 7.72 (s,1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H),7.10~7.12 (m, 2H), 6.51 (s, 1H), 6.00 (d, J = 4.0 Hz, 1H), 3.08 (s, 3H),2.91 (d, J = 4.0 Hz, 3H), 2.40 (s, 3H). 492 63

¹H-NMR (CDCl₃, 400 MHz) δ 7.94~7.98 (m, 2H), 7.78 (s, 1H), 7.73 (d, J =8.0 Hz, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.49~7.56 (m, 4H), 7.41 (d, J =3.2 Hz, 1H), 7.33~7.37 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.16-7.21 (m,2H), 6.72 (d, J = 2.8 Hz, 1H), 5.88 (br s, 1H), 3.09 (s, 3H), 2.95 (d, J= 4.8 Hz, 3H), 2.54 (s, 3H). 568 64

¹H-NMR (CDCl₃, 400 MHz) δ 8.28 (d, J = 8.0 Hz, 1H), 7.96~8.00 (m, 2H),7.93 (s, 1H), 7.60~7.63 (m, 3H), 7.49~7.52 (m, 2H). 7.16~7.20 (m, 4H),6.80~6.81 (d, J = 4.0 Hz, 1H), 6.57 (s, 1H), 3.18 (s, 3H), 3.00 (d, J =4.8 Hz. 3H), 2.68 (s, 3H). 587 65

¹H-NMR (CDCl₃, 400 MHz) δ 8.12~8.10 (m, 1H), 7.95~8.00 (m, 3H), 7.64 (s,1H), 7.47~7.64 (m, 4H), 7.18~7.22 (m, 2H), 6.73-6.79 (m, 2H), 6.16 (s,1H), 3.25 (s, 3H), 3.00 (d, J = 4.8 Hz, 3H), 2.60 (s, 3H). 605 66

¹H-NMR (MeOH, 400 MHz) δ 8.12~8.14 (d, J = 8.0 Hz, 1H), 7.95~7.98 (m,2H), 7.81 (s, 1H), 7.72~7.76 (m, 1H), 7.70~7.72 (d, J = 8.0 Hz, 1H),7.54~7.55 (m, 1H), 7.47~7.49 (d. J = 8.0 Hz, 1H), 7.21~7.26 (m, 4H),7.11~7.15 (m, 1H), 6.75 (s, 1H), 3.12 (s, 3H), 2.93 (d, J = 4.8 Hz, 3H),2.60 (s, 3H). 605

Example 4 Preparation of Compound 67

Step 1—Synthesis of 6-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole

NaH (65 mg, 1.63 mmol) was added to a solution of 6-chloro-1H-indole(200 mg, 1.32 mmol) in dry DMF (5 mL) under N₂. The mixture was allowedto stir at room temperature for 1 hour. Then1-(bromomethyl)-4-(trifluoromethyl)benzene (500 mg, 2.09 mmol) was addedto the reaction mixture, and the mixture was allowed to stir at roomtemperature for 30 mins. Ice cold NH₄Cl (sat. aq.) was added and themixture was extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and the solvent was evaporated underreduced pressure. The crude product was purified using columnchromatography to provide product6-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole (400 mg, yield: 97%).¹H-NMR (CDCl₃, 400 MHz) δ 7.5˜57.58 (m, 3H), 7.22 (s, 1H), 7.09˜7.17 (m,4H), 6.57 (br s, 1H), 5.33 (s, 2H). (M+H)⁺: 310.

Step 2—Synthesis of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole

To a solution of 6-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole (0.4g, 1.29 mmol) in dioxane (5 mL), KOAc (0.4 g, 4.08 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.5 g, 1.97mmol), Pd₂(dba)₃ (20 mg), X-Phos (20 mg) were added under N₂ protection.The mixture was heated at 100° C. for overnight. The mixture wasconcentrated in vacuo. The resulting residue was purified using columnchromatography (PE:EtOAc=10:1) to provide6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole(400 mg, yield: 77%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.79 (s, 1H), 7.68 (d,J=8.0 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 7.53˜7.56 (m, 2H), 7.14˜7.17 (m,3H), 6.59 (d, J=3.2 Hz, 1H), 5.44 (s, 2H), 1.35 (s, 12H). (M+H)⁺: 402.

Step 3—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(1-(4-(trifluoromethyl)benzyl)-1H-indol-6-yl)benzofuran-3-carboxamide

To a mixture of5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(Compound H, 60 mg, 0.13 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole(70 mg, 0.17 mmol) and K₃PO₄.3H₂O (70 mg, 0.26 mmol) in DMF (3 mL),Pd(dppf)Cl₂ (5 mg) was added under N₂ protection. The mixture was heatedat 80° C. for 4 hours. The reaction mixture was concentrated in vacuo,suspended in water and extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresulting residue was purified using prep-TLC to provide2-(4-fluorophenyl)-N-methyl-6-(N-carboxamide (50 mg, yield: 58%). ¹H-NMR(CDCl₃, 400 MHz) δ 7.9-27.97 (m, 2H), 7.76 (s, 1H), 7.70 (d, J=8.0 Hz,1H), 7.52˜7.55 (m, 3H), 7.41 (s, 1H), 7.16˜7.25 (m, 6H), 6.62 (d, J=2.4Hz, 1H), 5.89 (br s, 1H), 5.42 (s, 2H), 2.95 (br s, 6H), 2.51 (s, 3H).(M+H)⁺: 650.

Compounds 68-69, depicted in the table below, prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 68

¹H-NMR (CDCl₃, 400 MHz) δ 7.96 (t, J = 1.6 Hz, 2H), 7.74 (s, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.06~7.21 (m, 6H),6.95-7.03 (m, 2H), 6.58 (d, J = 2.4 Hz, 1H), 5.86 (s, 1H), 5.32 (s, 2H),2.97 (t, 6H), 2.43 (s, 3H). 600 69

¹H-NMR (CDCl₃, 400 MHz) δ 7.95~7.99 (m, 2H), 7.83 (s, 1H), 7.67 (d, J =8.0 Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.13~7.23 (m, 4H), 6.55 (d, J =3.2 Hz, 1H), 5.93 (br s, 1H), 4.31 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.2Hz. 2H), 3.01 (s, 3H), 2.97 (d, J = 4.8 Hz, 3H), 2.71 (s, 3H). 536

Example 5 Preparation of Compound 70

Step 1—Synthesis of 5-chloro-3-phenyl-1H-indole

In a screw-cap vial under air, a solution of 5-chloro-1H-indole (200 mg,1.32 mmol) and bromobenzene (249 mg, 1.58 mmol) in water (4 mL) wasadded Pd(OAc)₂ (15 mg), dppm (25 mg) and LiOH (166 mg, 2.96 mmol) underN₂. The mixture was heated to 110° C. and then stirred 24 hours. Thereaction mixture was cooled to room temperature and partitioned between1N HCl (5 mL) and EtOAc (10 mL). The layers were separated and theaqueous layer was further extracted with EtOAc (100 mL). The combinedorganic layer was washed with H₂O, brine, dried over Na₂SO₄. After beingconcentrated in vacuo, the resulting residue was purified using prep-TLC(PE:EtOAc=5:1) to provide 5-chloro-3-phenyl-1H-indole (150 mg, yield:50.0%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.10 (s, 1H), 7.80 (d, J=4.0 Hz, 1H),7.51˜7.53 (m, 2H), 7.34˜7.38 (m, 2H), 7.20˜7.25 (m, 3H), 7.09˜7.11 (m,1H). MS (M+H)⁺: 228/230.

Step 2—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-phenyl-1H-indol-5-yl)benzofuran-3-carboxamide

The procedure of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-phenyl-1H-indol-5-yl)benzofuran-3-carboxamidewas similar to that of Example 1. ¹H-NMR (CDCl₃, 400 MHz) δ 8.40 (s,1H), 7.94˜7.98 (m, 3H), 7.79 (s, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.61 (s,1H), 7.47 (d, J=8.0 Hz, 1H), 7.40˜7.44 (m, 3H), 7.24˜7.33 (m, 2H),7.15˜7.17 (m, 2H), 5.86 (d, J=4.0 Hz, 1H), 3.11 (s, 3H), 2.96 (d, J=4.0Hz, 3H), 2.51 (s, 3H). MS (M+H)⁺: 568.

Compound 71, depicted in the table below was prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 71

¹H-NMR (MeOH, 400 MHz) δ 8.78 (d, J = 4.0 Hz, 2H), 8.23 (d, J = 8.0 Hz,2H), 8.02 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.79 (d, J =4.0 Hz, 2H), 7.67 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.23~7.27 (m, 2H),6.97 (s, 1H), 3.13 (s, 3H), 2.92 (s, 3H), 2.85 (s, 3H). 569

Example 6 Preparation of Compound 72 & 73

Step 1—Synthesis of 5-bromo-3-iodo-1H-indazole

KOH (4.27 g, 76.13 mmol) was added into a solution of5-bromo-1H-indazole (5.0 g, 25.38 mmol) and I₂ (12.9 g, 50.75 mmol) inDMF (10 mL) and stirred at room temperature for 12 hours. After beingdiluted with ice-water and extracted with EtOAc (50 mL×3), and thecombined organic phase was washed with brine, dried over Na₂SO₄ andconcentrated to provide the desired product of5-bromo-3-iodo-1H-indazole (8 g, yield: 90.0%). And it was used for thenext step without further purification.

Step 2—Synthesis of tert-butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate

To a solution of 5-bromo-3-iodo-1H-indazole (8.0 g, 24.7 mmol), Et₃N(3.76 g, 37.2 mmol) and DMAP (151 mg, 1.24 mmol) in dry DCM (70 mL) wasallowed to stir at 25° C. Boc₂O (5.95 g, 27.3 mmol) was added. Themixture was allowed to stir to at 25° C. for overnight.

The solvent was removed in vacuo and the resulting residue was purifiedusing column chromatography (PE:EtOAc=50:1) to provide tert-butyl5-bromo-3-iodo-1H-indazole-1-carboxylate (7.0 g, yield: 77.8%). ¹H-NMR(CDCl₃, 400 MHz) δ 7.94 (d, J=8.0 Hz, 1H), 7.5˜87.61 (m, 2H), 1.64 (s,9H). MS (M+H)⁺: 423/425.

Step 3—Synthesis of tert-butyl5-bromo-3-(4-fluorophenyl)-1H-indazole-1-carboxylate

To a degassed solution of tert-butyl5-bromo-3-iodo-1H-indazole-1-carboxylate (423 mg, 1.0 mmol) and4-fluorophenylboronic acid (168 mg, 1.2 mmol) in dry ethanol:toluene(1:10 mL) was added Pd(dppf)Cl₂ (3 mg) and Na₂CO₃(4 mL, 2.0 mmol) underN₂. The mixture was heated to 100° C. and then stirred overnight. Thereaction mixture was cooled to room temperature and filtered. Thefiltrate was washed with EtOAc, brine, dried over Na₂SO₄. After beingconcentrated in vacuo, the resulting residue was purified usingprep-HPLC to provide tert-butyl5-bromo-3-(4-fluorophenyl)-1H-indazole-1-carboxylate (20 mg, yield:29%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.03 (d, J=8.0 Hz, 1H), 7.99 (d, J=4.0Hz, 1H), 7.84˜7.88 (m, 2H), 7.5˜67.59 (m, 1H), 7.13˜7.19 (m, 2H), 1.67(s, 9H). MS (M+H)⁺: 391/393.

Step 4—Synthesis of tert-butyl3-(4-fluorophenyl)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-1H-indazole-1-carboxylate

To a degassed solution of tert-butyl5-bromo-3-(4-fluorophenyl)-1H-indazole-1-carboxylate (100 mg, 0.26 mmol)and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 128 mg, 0.25 mmol) in dry dioxane (5 mL) was addedPd(dppf)Cl₂ (5 mg) and K₃PO₄ (204 mg, 0.77 mmol) under N₂. The mixturewas heated to 100° C. and stirred overnight. The reaction mixture wascooled to room temperature and filtered. The filtrate was diluted withEtOAc, washed with brine, dried over Na₂SO₄. After being concentrated invacuo, the resulting residue was purified using prep-HPLC to providetert-butyl3-(4-fluorophenyl)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-1H-indazole-1-carboxylate(100 mg, yield: 56.8%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.23 (d, J=8.0 Hz,1H), 8.00˜8.05 (m, 3H), 7.90˜7.94 (m, 2H), 7.88 (s, 1H), 7.63˜7.65 (m,1H), 7.59 (s, 1H), 7.1˜77.22 (m, 4H), 5.85 (d, J=4.0 Hz, 1H), 3.07 (s,3H), 2.96 (d, J=4.8 Hz, 3H), 2.73 (s, 3H), 1.79 (s, 9H). MS (M+H)⁺: 687.

Step 5—Synthesis of2-(4-fluorophenyl)-5-(3-(4-fluorophenyl)-1H-indazol-5-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

TFA (1 mL) was added into a solution of tert-butyl3-(4-fluorophenyl)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-1H-indazole-1-carboxylate(50 mg, 0.07 mmol) in DCM (10 mL) under N₂ dropwise at 0° C. and themixture was allowed to stir at room temperature for 6 hours. After beingdiluted with NaHCO₃ (a.q) and extracted with EtOAc (50 mL×3), thecombined organic phase was washed with brine, dried over Na₂SO₄ andconcentrated to provide the desired product of2-(4-fluorophenyl)-5-(3-(4-fluorophenyl)-1H-indazol-5-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(30 mg, yield: 69.7%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.99 (s, 1H), 7.84˜7.91(m, 4H), 7.80 (s, 1H), 7.53 (s, 1H), 7.42˜7.48 (m, 2H), 7.03˜7.16 (m,4H), 5.85 (d, J=4.8 Hz, 1H), 3.01 (s, 3H), 2.90 (d, J=4.8 Hz, 3H), 2.64(s, 3H). MS (M+H)⁺: 587.

Compounds 74-76, depicted in the table below, prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 74

¹H-NMR (CDCl₃, 400 MHz) δ 8.48 (s, 2H), 8.19 (s, 2H), 8.09 (s, 1H),7.82~7.85 (m, 2H), 7.76 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H),7.44 (d, J = 8.0 Hz, 1H), 7.08~7.13 (m. 2H), 2.97 (s, 3H), 2.92 (s, 3H),2.90 (s, 3H). 570 75

¹H-NMR (CDCl₃, 400 MHz) δ 8.03 (d, J = 8.0 Hz, 3H), 7.81~7.86 (m, 3H),7.65 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H), 7.40~7.48 (m, 2H), 7.11~7.19 (m,2H), 5.89 (d, J = 4.0 Hz, 1H), 3.00 (s, 3H), 2.90 (d, J = 4.0 Hz, 3H),2.68 (s, 3H). 637 76

¹H-NMR (CDCl₃, 400 MHz) δ 7.97 (s, 1H), 7.81~7.84 (m, 4H), 7.77 (s, 1H),7.51 (s, 1H), 7.39~7.41 (m, 1H), 7.34~7.36 (m, 3H), 7.09~7.18 (m, 2H),5.98 (d, J = 4.8 Hz, 1H), 2.98 (s, 3H), 2.88 (d, J = 4.8 Hz, 3H), 2.63(s, 3H). 603

Example 7 Preparation of Compound 77

Step 1—Synthesis of ethyl5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylate

4-chlorobutanoyl chloride (670 mg, 4.76 mmol) was added dropwise at 0°C. to a solution of ethyl6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate and Et₃N (1.0mL) in CH₂Cl₂ (10 mL) under N₂ protection and the mixture was allowed tostir at room temperature for 16 hours. The reaction mixture wasconcentrated to provide the resulting residue. A mixture of theresulting residue, K₂CO₃ (658 mg, 4.76 mmol) and KI (263 mg, 1.59 mmol)in CH₃CN (10 mL) was refluxed for 16 hours. After cooled, the mixturewas diluted with water and extracted with EtOAc. The combined organicphases were washed with brine, dried over Na₂SO₄, filtered andevaporated. The crude product was purified using column chromatography(PE:EtOAc=2:1) to provide pure ethyl5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylate(280 mg, yield: 40%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.32 (s, 1H), 8.0˜48.07(m, 2H), 7.48 (s, 1H), 7.17˜7.21 (m, 2H), 4.42˜4.43 (m, 2H), 3.82˜3.86(m, 2H), 2.6˜12.65 (m, 2H), 2.27˜2.31 (m, 2H), 1.40˜1.44 (m, 3H). MS(M+H)⁺: 446/448.

Step 2—Synthesis of5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylicacid

A solution of ethyl5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylate(2.5 g, 5.80 mmol) and LiOH (0.5 g, 21.0 mmol) in dioxane (30 mL) andwater (10 mL) was allowed to stir at 90° C. for 1 hour. The mixture wasquenched with ice and extracted with DCM, the organic layer was washedwith brine, dried over Na₂SO₄ and concentrated to provide5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylicacid (2.2 g, yield: 91%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.08 (s, 1H),7.81˜7.84 (m, 2H), 7.34 (s, 1H), 6.89˜6.93 (m, 2H), 3.79˜3.82 (m, 2H),2.66˜2.70 (m, 2H), 2.26˜2.31 (m, 2H). MS (M+H)⁺: 418/420.

Step 3—Synthesis of5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide

A solution of5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylicacid (280 mg, 0.67 mmol), HOBT (150 mg, 1.11 mmol) and EDCI (280 mg,1.47 mmol) in dry DMF (2 mL) was allowed to stir at room temperature for1 hour. Then Et₃N (0.2 mL) and CH₃NH₂ (HCl salt, 100 mg, 1.48 mmol) wasadded to the mixture, the resultant mixture was allowed to stirovernight. After the solvent was removed, water was added and themixture was extracted with ethyl acetate. The combined organic layer waswashed with brine, dried and concentrated in vacuo. The resultingresidue was purified using column chromatography (PE:EtOAc=1:1) toprovide5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide(220 mg, yield: 73%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.94 (s, 1H), 7.8˜27.86(m, 2H), 7.32 (s, 1H), 7.09˜7.14 (m, 2H), 6.29 (s, 1H), 3.75˜3.78 (m,2H), 2.97 (d, J=4.8 Hz, 3H), 2.56˜2.60 (m, 2H), 2.24˜2.26 (m, 2H). MS(M+H)⁺: 431/433.

Step 4—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-1-yl)-5-(1-phenyl-1H-benzo[d]imidazol-6-yl)benzofuran-3-carboxamide

To a mixture of5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide(70 mg, 0.16 mmol), K₃PO₄.3H₂O (108 mg, 0.41 mmol) and1-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(40 mg, 0.16 mmol, prepared from corresponding bromide intermediate ofCompound 2, using the method described in step 2 of Example 4) in DMF (1mL), Pd(dppf)Cl₂ (10 mg) was added under N₂ protection. The mixture wasallowed to stir at 100° C. for 16 hours. After the mixture was filteredand concentrated, the resulting residue was purified using prep-HPLC toprovide2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-1-yl)-5-(1-phenyl-1H-benzo[d]imidazol-6-yl)benzofuran-3-carboxamide(10 mg, yield: 11%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.11 (s, 1H), 7.8˜17.89(m, 3H), 7.76 (s, 1H), 7.51˜7.54 (m, 3H), 7.40˜7.48 (m, 4H), 7.29˜7.31(m, 1H), 7.1˜07.14 (m, 2H), 5.83˜5.85 (br s, 1H), 3.12˜3.15 (m, 2H),2.89 (d, J=4.8 Hz, 3H), 2.27˜2.31 (m, 2H), 1.73˜1.77 (m, 2H). MS (M+H)⁺:545.

Example 8 Preparation of Compound 78

Step 1—Synthesis of6-bromo-1-(3,5-difluorophenyl)-4-methoxy-1H-benzo[d]imidazol-2-amine

To a solution of5-bromo-N¹-(3,5-difluorophenyl)-3-methoxybenzene-1,2-diamine (500 mg,0.32 mmol, prepared using similar method described in the Example 1) inMeOH (15 mL) was added BrCN (750 mg, 0.63 mmol) and the mixture washeated at 60° C. for 10 hours. Then the mixture was concentrated,diluted with water, and extracted with DCM. The organics were dried overNa₂SO₄ and concentrated to give crude product of6-bromo-1-(3,5-difluorophenyl)-4-methoxy-1H-benzo[d]imidazol-2-amine(500 mg, yield: 93%), which was used for next step without furtherpurification. ¹H-NMR (CDCl₃, 400 MHz) δ 6.9-27.00 (m, 3H), 6.78 (s, 2H),4.98 (s, 2H), 3.91 (s, 3H). (M+H)⁺: 354/356.

Step 2—Synthesis of5-(2-amino-1-(3,5-difluorophenyl)-4-methoxy-1H-benzo[d]imidazol-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of6-bromo-1-(3,5-difluorophenyl)-4-methoxy-1H-benzo[d]imidazol-2-amine (77mg, 0.22 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 100 mg, 0.2 mmol) in 1,4-dioxane (2 mL) were addedPd(dppf)Cl₂ (10 mg) and K₂CO₃ (41 mg, 0.3 mmol) under N₂. The mixturewas heated at 100° C. overnight. The reaction mixture was cooled to roomtemperature, filtered and washed with EtOAc. The filtrate was washedwith H₂O, brine, dried over Na₂SO₄ and concentrated, the residue waspurified by prep-TLC (DCM:EtOAc=1:1) to give5-(2-amino-1-(3,5-difluorophenyl)-4-methoxy-1H-benzo[d]imidazol-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(20 mg, yield: 18%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.8-57.89 (m, 2H), 7.73(s, 1H), 7.45 (s, 1H), 7.12 (t, J=8.4 Hz, 2H), 7.06˜7.08 (m, 2H),6.85˜6.89 (m, 1H), 6.79 (d, J=4.4 Hz, 2H), 5.90 (d, J=4.8 Hz, 1H), 4.84(s, 2H), 3.95 (s, 3H), 2.93 (s, 3H), 2.91 (d, J=5.2 Hz, 3H), 2.75 (s,3H). (M+H)⁺: 650.

Compound 79, depicted in the table below, was prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 79

¹H-NMR (Methanol-d4, 400 MHz) δ 8.46~8.47 (m, 1H), 7.91~7.95 (m, 2H),7.83 (s, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 6.0 Hz, 2H),7.23~7.34 (m, 3H), 7.13 (s, 1H), 3.07 (s, 3H), 3.03 (s, 3H), 2.91 (d, J= 4.0 Hz, 3H). 638

Example 9 Preparation of Compound 80

Step 1—Synthesis of6-bromo-1-(3,5-difluorophenyl)-4-methoxy-1H-benzo[d]imidazol-2(3H)-one

To a solution of5-bromo-N¹-(3,5-difluorophenyl)-3-methoxybenzene-1,2-diamine (500 mg,0.32 mmol) in DCM (13 mL) was added triphosgene (835 mg, 0.63 mmol) andthe mixture was heated at 40° C. for 8 hours under N₂. Then the mixturewas concentrated and diluted with water. After extracted with DCM, theorganics were dried over Na₂SO₄ and concentrated to give crude productof6-bromo-1-(3,5-difluorophenyl)-4-methoxy-1H-benzo[d]imidazol-2(3H)-one(500 mg, yield: 93%), which was used for next step without furtherpurification. ¹H-NMR (CDCl₃, 400 MHz) δ 7.92 (s, 1H), 7.06 (d, J=5.6 Hz,2H), 6.86 (s, 1H), 6.7˜96.82 (m, 2H), 3.87 (s, 3H). (M+H)⁺: 355/357.

Step 2—Synthesis of5-(3-(3,5-difluorophenyl)-7-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of6-bromo-1-(3,5-difluorophenyl)-4-methoxy-1H-benzo[d]imidazol-2(3H)-one(77 mg, 0.22 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 100 mg, 0.2 mmol) in 1,4-dioxane (2 mL) were addedPd(dppf)Cl₂ (10 mg) and K₂CO₃ (41 mg, 0.3 mmol) under N₂. The mixturewas heated at 100° C. overnight. The reaction mixture was cooled to roomtemperature, filtered and washed with EtOAc. The filtrate was washedwith H₂O, brine, dried over Na₂SO₄ and concentrated, the residue waspurified by prep-TLC (DCM:EtOAc=1:1) to give5-(3-(3,5-difluorophenyl)-7-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(30 mg, yield: 21%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.8-47.88 (m, 2H), 7.75(d, J=4.4 Hz, 1H), 7.45 (s, 1H), 7.12˜7.18 (m, 4H), 7.12 (s, 1H), 6.89(s, 1H), 6.74˜6.80 (m, 1H), 5.74 (s, 1H), 3.91 (s, 3H), 2.97 (s, 3H),2.91 (d, J=5.6 Hz, 6H). (M+H)⁺: 651.

Compounds 81-82, depicted in the table below, were prepared using themethod described above and substituting the appropriate reactants andreagents.

MS Compound Structure NMR (M + H)⁺ 81

¹H-NMR (CDCl₃, 400 MHz) δ 8.16 (s, 1H), 7.87~7.91 (m, 2H), 7.81 (s, 1H),7.50 (d, J = 8.4 Hz, 1H), 7.14~7.24 (m, 5H), 7.03 (d, J = 6.8 Hz, 1H),6.80~6.85 (m, 1H), 5.78 (s. 1H), 3.10 (s, 3H), 2.96 (d, J = 4.8 Hz, 3H),2.91 (s, 3H). 639 82

¹H-NMR (CDCl₃, 400 MHz) δ 7.84~7.87 (m, 3H), 7.72 (d, J = 3.2 Hz, 1H),7.47~7.54 (m, 2H), 7.45 (s, 1H), 7.08~7.15 (m, 7H), 5.71 (d, J = 7.6 Hz,1H), 2.98 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H), 2.76 (s, 3H). 603

Example 10 Preparation of Compound 83

Step 1—Synthesis of (5-bromo-2-hydroxyphenyl)(phenyl)methanone

To a melt of 4-bromophenyl benzoate (4 g, 14.4 mmol) was added powderedaluminum trichloride (3.84 g, 28.8 mmol) and the mixture was heated at150° C. for 3 h. To the residue was added 6 M of HCl and EtOAc. Theorganic phase was washed with brine, dried over sodium sulfate andconcentrated in vacuo to give (5-bromo-2-hydroxyphenyl)(phenyl)methanone(3.2 g, yield: 80%) through column chromatography (PE:EtOAc=10:1).¹H-NMR (DMSO-d₆, 400 MHz) δ 10.38 (s, 1H), 7.70˜7.72 (m, 2H), 7.63˜7.67(m, 1H), 7.44˜7.57 (m, 3H), 7.43 (s, 1H), 6.91 (d, J=8.8 Hz, 1H).(M+H)⁺: 277/279.

Step 2—Synthesis of (E)-(5-bromo-2-hydroxyphenyl)(phenyl)methanone oxime

A solution of (5-bromo-2-hydroxyphenyl)(phenyl)methanone (2.0 g, 7.2mmol) and hydroxylamine hydrochloride (3.52 g, 50.6 mmol) in 10 mL ofpyridine and 60 mL of EtOH was heated to reflux for 16 h. The mixturewas concentrated in vacuo and the residue was suspended in 1 M of HCl,then extracted with EtOAc. The organic phase was washed with brine,dried over sodium sulfate and concentrated in vacuo to give the pure(E)-(5-bromo-2-hydroxyphenyl)(phenyl)methanone oxime (670 mg, yield:32%) through column chromatography (PE:EtOAc=10:1). ¹H-NMR (DMSO-d₆, 400MHz) δ 11.8 (s, 1H), 11.2 (s, 1H), 7.45˜7.51 (m, 3H), 7.34˜7.41 (m, 3H),6.89˜6.91 (m, 2H). (M+H)⁺: 292/294.

Step 3—Synthesis of 5-bromo-3-phenylbenzo[d]isoxazole

DDQ (116 mg, 0.51 mmol) and PPh₃ (135 mg, 0.51 mmol) were dissolved inDCM (5 mL) and the mixture was stirred for 10 minutes. Then(E)-(5-bromo-2-hydroxyphenyl)(phenyl)methanone oxime (100 mg, 0.34 mmol)was added and the mixture was stirred at room temperature for 2 h.Finally the mixture was concentrated in vacuo to give5-bromo-3-phenylbenzo[d]isoxazole (90 mg, yield: 95%) through columnchromatography (PE:EtOAc=10:1). ¹H-NMR (DMSO-d6, 400 MHz) δ 8.19 (d,J=6.8 Hz, 2H), 8.06 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.58˜7.67 (m, 4H).(M+H)⁺: 274/276.

Step 4—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-phenylbenzo[d]isoxazol-5-yl)benzofuran-3-carboxamide

To a solution of 5-bromo-3-phenylbenzo[d]isoxazole (90 mg, 0.33 mmol),2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 150 mg, 0.30 mmol) and K₃PO₄.3H₂O (159 mg, 0.60 mmol) in 2mL of dioxane and 0.2 mL of water was added Pd(dppf)Cl₂ (10 mg) undernitrogen. The mixture was heated at 100° C. for 4 h, then concentratedin vacuo and the residue was suspended in water. The mixture wasextracted with EtOAc and the organic phase was washed with brine, driedover sodium sulfate.2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-phenylbenzo[d]isoxazol-5-yl)benzofuran-3-carboxamide(120 mg, yield: 70%) was obtained after the prep-TLC (DCM:MeOH=30:1).¹H-NMR (CDCl₃, 400 MHz) δ 8.2˜78.29 (m, 2H), 7.94˜7.97 (m, 2H), 7.84 (s,1H), 7.81 (s, 1H), 7.63˜7.67 (m, 2H), 7.52˜7.56 (m, 3H), 7.46˜7.48 (m,1H), 7.20 (t, J=8.8 Hz, 2H), 5.88 (brs, 1H), 3.18 (s, 3H), 2.98 (d,J=4.8 Hz, 3H), 2.60 (s, 3H). (M+H)⁺: 570.

Example 11 Preparation of Compound 84

Step 1—Synthesis of 5-bromo-2-(4-fluorobenzyl)oxazolo[4,5-b]pyridine

PPA (2 mL) was heated at 130° C., and then 2-(4-fluorophenyl)acetic acid(400 mg, 2.6 mmol) and 2-amino-6-bromopyridin-3-ol (589 mg, 3.1 mmol)were added under N₂ protection. After stirred at 130° C. for 4 hours,the mixture was quenched with ice and NaOH (aq). Then the mixture wasextracted with EtOAc, dried over Na₂SO₄, filtrated and concentrated. Theresidue was purified by column chromatography (PE:EtOAc=15:1 to 10:1) togive the product of 5-bromo-2-(4-fluorobenzyl)oxazolo[4,5-b]pyridine(200 mg, yield: 25%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.61 (d, J=8.4 Hz, 1H),7.41 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.0, 5.6 Hz, 2H), 7.02 (t, J=8.0 Hz,2H), 4.28 (s, 2H). MS (M+H)⁺: 307/309.

Step 2—Synthesis of5-(2-(4-fluorobenzyl)oxazolo[4,5-b]pyridin-5-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of5-bromo-2-(4-fluorobenzyl)oxazolo[4,5-b]pyridine (100 mg, 0.32 mmol),2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 196 mg, 0.39 mmol) and K₃PO₄.3H₂O (174 mg, 0.65 mmol) in1,4-dioxane (2 mL) was added Pd(dppf)Cl₂ (20 mg) under N₂ protection.The reaction mixture was stirred at 100° C. for 16 hours. After filteredthrough a celite pad, the filtrate was concentrated. The residue waspurified by basic prep-HPLC to give the product of5-(2-(4-fluorobenzyl)oxazolo[4,5-b]pyridin-5-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(20 mg, yield: 10%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.8˜97.93 (m, 3H), 7.78(d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.35 (dd,J=8.8, 5.6 Hz, 2H), 7.13 (t, J=8.8 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 5.87(d, J=4.8 Hz, 1H), 4.27 (s, 2H), 3.13 (s, 3H), 2.92 (d, J=4.8 Hz, 3H),2.78 (s, 3H). MS (M+H)⁺: 603.

Compounds 85-87, depicted in the table below, were prepared using themethod described above and substituting the appropriate reactants andreagents.

MS Compound Structure NMR (M + H)⁺ 85

¹H NMR: (CDCl₃, 400 MHz): 8.15 (d, J = 6.8 Hz s, 2 H), 7.92~7.96 (m,3H), 7.78 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.38~7.50 (m, 5H), 7.24 (s,1H)), 7.19 (t, J = 8.4 Hz, 1H), 5.94 (brs, 1H), 3.20 (s, 3H), 2.94 (d, J= 4.8 Hz, 3H), 2.34 (s, 3H). 570 86

¹H-NMR (CDCl₃, 400 MHz) δ 8.12 (t, J = 6.4 Hz, 2H), 7.87~7.91 (m, 3H),7.73 (d, J = 7.2 Hz, 1H), 7.65 (s, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.35(t, J = 8.0 Hz, 1H), 7.16 (t, J = 8.4 Hz, 2H), 7.10 (t, J = 8.0 Hz, 2H),5.81 (brs, 1H), 3.12 (s, 3H), 2.91 (d, J = 4.8 Hz, 3H), 2.35 (s, 3H).588 87

¹H-NMR (DMSO-d6, 400 MHz) δ 8.50 (d, J = 4.4 Hz, 1H), 8.26 (dd, J₁ = 8.8Hz, J₂ = 5.6 Hz, 2H), 7.98~8.01 (m, 3H), 7.82~7.85 (m, 2H), 7.62 (s,1H), 7.43~7.49 (m, 3H), 7.39 (t, J = 8.8 Hz, 2H), 3.08 (s, 3H), 2.94 (s,3H), 2.78 (d, J = 4.4 Hz, 3H). 588

Example 12 Preparation of Compound 88

Step 1—Synthesis of 6-bromo-2-phenylimidazo[1,2-a]pyridine

A solution of 5-bromopyridin-2-amine (1.0 g, 5.78 mmol),2-bromoacetophenone (1.4 g, 7.03 mmol) in MeOH (20 mL) was heated at 80°C. overnight. The reaction mixture was concentrated in vacuo. Theresidue was suspended with water, and extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatography(PE:EtOAc=5:1 to 2:1) to give product of6-bromo-2-phenylimidazo[1,2-a]pyridine (800 mg, yield: 50%). ¹H-NMR(CDCl₃, 400 MHz) δ 8.27 (d, J=0.8 Hz, 1H), 7.93˜7.95 (m, 2H), 7.84 (s,1H), 7.53 (d, J=9.6 Hz, 1H), 7.42˜7.47 (m, 2H), 7.33˜7.37 (m, 1H),7.22˜7.25 (m, 1H). MS (M+H)⁺: 273/275.

Step 2—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(2-phenylimidazo[1,2-a]pyridin-6-yl)benzofuran-3-carboxamide

The procedure of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(2-phenylimidazo[1,2-a]pyridin-6-yl)benzofuran-3-carboxamide(30 mg, yield: 24%) was similar to step 4 of Example 1. ¹H NMR (CDCl₃,400 MHz) δ 8.38 (s, 1H), 7.89˜7.93 (m, 2H), 7.87 (s, 1H), 7.81 (d, J=5.6Hz, 2H), 7.55˜7.58 (m, 2H), 7.47 (s, 1H), 7.27˜7.32 (m, 3H), 7.1˜47.22(m, 4H), 3.10 (d, J=4.8 Hz, 3H), 3.04 (s, 3H), 2.98 (s, 3H). MS (M+H)⁺:569.

Compound 89, depicted in the table below, was prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 89

¹H-NMR (CDCl₃, 400 MHz) δ 8.13~8.17 (m, 1H), 7.87~7.95 (m, 5H),7.79~7.83 (m, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H),7.39~7.45 (m, 2H), 7.31~7.34 (m, 1H), 7.17~7.21 (m, 2H), 7.02~7.06 (m,1H), 6.19 (br s, 1H), 3.16 (d, J = 4.8 Hz, 3H), 3.02 (d, J = 4.8 Hz,3H), 2.90 (s, 3H). 569

Example 13 Preparation of Compound 90

Step 1—Synthesis of 6-bromoimidazo[1,2-a]pyrazine

To a degassed solution of 5-bromopyrazin-2-amine (2.0 g, 0.13 mmol) andHBr (aq, 0.5 mL) in propan-2-ol (50 mL) was added2-bromo-1,1-dimethoxyethane (3.9 g, 22.9 mmol). The reaction was heatedto 80° C. for 10 hours. The reaction mixture was cooled to RT andextract with DCM. The organics were washed with NaHCO₃ (aq), brine anddried over Na₂SO₄. After concentrated, the crude product of6-bromoimidazo[1,2-a]pyrazine (2.1 g, yield: 75%), which was used fornext step without purification. ¹H-NMR (CDCl₃, 400 MHz) δ 8.86 (s, 1H),8.24 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H). MS (M+H)⁺: 198/200.

Step 2—Synthesis of2-(4-fluorophenyl)-5-(imidazo[1,2-a]pyrazin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

A solution of 6-bromoimidazo[1,2-a]pyrazine (80 mg, 0.4 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 200 mg, 0.2 mmol) in dry DMF (10 mL) was added Pd(dppf) Cl₂(10 mg) and K₃PO₄ (80 mg, 0.38 mmol) under N₂. The mixture was heated to80° C. and then stirred overnight. The reaction mixture was cooled toroom temperature and filtered. After concentrated, the residue waspurified by prep-HPLC to give the product of2-(4-fluorophenyl)-5-(imidazo[1,2-a]pyrazin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(66 mg, yield: 34%). ¹H-NMR (CDCl₃, 400 MHz) δ 9.61 (s, 1H), 8.71 (s,1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.91˜7.95 (m, 3H), 7.61 (s, 1H),7.2˜17.25 (m, 2H), 6.21 (s, 1H), 3.25 (s, 3H), 3.01 (s, 3H), 3.00 (s,3H). MS (M+H)⁺: 494.

Example 14 Preparation of Compound 91

Step 1—Synthesis of 6-bromo-3-iodoimidazo[1,2-a]pyrazine

A degassed solution of 6-bromoimidazo[1,2-a]pyrazine (500 mg, 2.52 mmol)and NIS (852 mg, 3.79 mmol) in DMF (10 mL) was heated to 60° C. for 10hours. The reaction mixture was cooled to RT and extract with DCM. Theorganics were washed with Na₂S₂O₃ (aq), brine and dried over Na₂SO₄.After concentrated, the crude product was purified by column(PE:EtOAc=5:1) to obtain 6-bromo-3-iodoimidazo[1,2-a]pyrazine (530 mg,yield: 65%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.75 (s, 1H), 8.18 (s, 1H), 7.82(s, 1H). MS (M+H)⁺: 324/326.

Step 2—Synthesis of 6-bromo-3-(4-fluorophenyl)imidazo[1,2-a]pyrazine

To a degassed solution of 6-bromo-3-iodoimidazo[1,2-a]pyrazine (100 mg,0.31 mmol) and 4-fluorophenylboronic acid (43 mg, 0.31 mmol) in1,4-dioxane (3 mL) were added Pd(dppf)Cl₂ (10 mg) and K₂CO₃ (77 mg, 0.56mmol) under N₂. The mixture was heated to 100° C. overnight. Aftercooled to RT and filtered, the filtrate was washed with brine, driedover Na₂SO₄ and concentrated, the residue was purified by prep-TLC(PE:EtOAc=5:1) to give 6-bromo-3-(4-fluorophenyl)imidazo[1,2-a]pyrazine(50 mg, yield: 22%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.06 (t, J=6.8 Hz, 2H),7.45˜7.48 (m, 1H), 7.23 (t, J=8.8 Hz, 1H), 7.07 (t, J=8.4 Hz, 3H). MS(M+H)⁺: 292/294.

Step 3—Synthesis of2-(4-fluorophenyl)-5-(3-(4-fluorophenyl)imidazo[1,2-a]pyrazin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of6-bromo-3-(4-fluorophenyl)imidazo[1,2-a]pyrazine (78 mg, 0.27 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 150 mg, 0.3 mmol) in 1,4-dioxane (3.0 mL) were addedPd(dppf)Cl₂ (10 mg) and K₃PO₄ (126 mg, 0.6 mmol) under N₂. The mixturewas heated to 100° C. overnight. The reaction mixture was cooled to RTand filtered. The filtrate was washed with H₂O, brine, dried overNa₂SO₄. After concentrated, the residue was purified by prep-TLC(PE:EtOAc=1:1) to give2-(4-fluorophenyl)-5-(3-(4-fluorophenyl)imidazo[1,2-a]pyrazin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(30 mg, yield: 18%). ¹H-NMR (CDCl₃, 400 MHz) δ 9.27 (s, 1H), 8.64 (s,1H), 8.03 (s, 1H), 7.89˜7.92 (m, 3H), 7.59˜7.62 (m, 2H), 7.52 (s, 1H),7.20 (t, J=8.8 Hz, 2H), 7.14 (t, J=8.8 Hz, 2H), 5.99 (d, J=4.0 Hz, 1H),3.17 (s, 3H), 2.95 (s, 3H), 2.92 (d, J=4.8 Hz, 3H). MS (M+H)⁺: 588.

Compounds 92-93, depicted in the table below, were prepared using themethod described above and substituting the appropriate reactants andreagents.

MS Compound Structure NMR (M + H)⁺ 92

¹H-NMR (CDCl₃, 400 MHz) δ 9.21 (s, 1H), 8.71 (s, 1H), 8.04 (s, 1H), 7.95(s, 1H), 7.88~7.92 (m, 2H), 7.74~7.79 (m, 4H), 7.53 (s, 1H), 7.14 (t, J= 8.8 Hz, 2H), 5.82 (s, 1H), 3.18 (s, 3H), 2.97 (s, 3H), 2.92 (d, J =4.8 Hz, 3H). 638 93

¹H-NMR (CDCl₃, 400 MHz) δ 9.35 (s, 1H), 8.69 (s, 1H), 8.04 (s, 1H), 7.95(s, 1H), 7.89~7.93 (m, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.53 (s, 1H), 7.49(d, J = 8.0 Hz, 2H), 7.15 (t, J = 8.4 Hz, 2H), 5.95 (s, 1H), 3.18 (s,3H), 2.97 (s, 3H), 2.93 (d, J = 4.8 Hz, 3H). 604

Example 15 Preparation of Compound 94

Step 1—Synthesis of 6-chloroimidazo[1,2-b]pyridazine

To a degassed solution of 6-chloropyridazin-3-amine (5.0 g, 38.6 mmol)and HBr (aq, 0.5 mL) in 2-bromo-1,1-dimethoxyethane (15.2 g, 77.2 mmol)in propan-2-ol (50 mL) was heated to 90° C. for 10 hours. The reactionmixture was cooled to RT and extract with DCM. The organics were washedwith NaHCO₃ (aq), brine and dried over Na₂SO₄. After concentrated, thecrude product of 6-chloroimidazo[1,2-b]pyridazine (4.7 g, yield: 80%),which was used to next step with no purification. ¹H-NMR (CDCl₃, 400MHz) δ 7.90 (s, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.76 (s, 1H), 7.00 (d,J=9.6 Hz, 1H). MS (M+H)⁺: 154.

Step 2—Synthesis of 6-chloro-3-iodoimidazo[1,2-b]pyridazine

To a degassed solution of 6-chloroimidazo[1,2-b]pyridazine (1.0 g, 6.51mmol) and NIS (2.2 g, 9.77 mmol) in MeCN (30 mL) was heated to 60° C.for 10 hours. The reaction mixture was cooled to RT and extract withDCM. The organics were washed with Na₂S₂O₃ (aq), brine and dried overNa₂SO₄. After concentrated, the crude product was purified by column(PE:EA=5:1) to obtain 6-chloro-3-iodoimidazo[1,2-b]pyridazine (1.4 g,yield: 83%). ¹H-NMR (CDCl₃, 400 MHz) δ 7.83 (s, 1H), 7.80 (d, J=4.8 Hz,1H), 7.04 (d, J=9.6 Hz, 1H). MS (M+H)⁺: 280.

Step 3—Synthesis of6-chloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine

To a degassed solution of 6-chloro-3-iodoimidazo[1,2-b]pyridazine (100mg, 0.36 mmol) and 4-(trifluoromethyl)phenylboronic acid (82 mg, 0.43mmol) in 1,4-dioxane (10.0 mL) was added Pd(dppf)Cl₂ (10 mg) and K₃PO₄(98 mg, 0.72 mmol) under N₂. The mixture was heated to 100° C.overnight. The reaction mixture was cooled to RT and filtered. Thefiltrate was washed with H₂O, brine, dried over Na₂SO₄. Afterconcentrated, the residue was purified by Prep-TLC to give6-chloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (95 mg,yield: 84%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.12 (s, 2H), 8.09 (d, J=6.8 Hz,1H), 7.98 (d, J=9.2 Hz, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.11 (d, J=9.2 Hz,1H). MS (M+H)⁺: 298.

Step 4—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)benzofuran-3-carboxamide

To a degassed solution of6-chloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (71 mg,0.24 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 100 mg, 0.2 mmol) in 1,4-dioxane (2.0 mL) was addedPd(dppf)Cl₂ (10 mg) and K₃PO₄ (63 mg, 0.3 mmol) under N₂. The mixturewas heated to 100° C. overnight. The reaction mixture was cooled to RTand filtered. The filtrate was washed with H₂O, brine, dried overNa₂SO₄. After concentrated, the residue was purified by prep-TLC to give2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)benzofuran-3-carboxamide(40 mg, yield: 30%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.33 (d, J=9.6 Hz, 1H),8.05˜8.11 (m, 4H), 7.83˜7.87 (m, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.62 (s,1H), 7.57 (t, J=5.6 Hz, 2H), 7.16 (d, J=8.8 Hz, 1H), 5.75 (d, J=6.8 Hz,1H), 3.21 (s, 3H), 2.91 (d, J=4.8 Hz, 3H), 2.80 (s, 3H). MS (M+H)⁺: 638.

Compound 95, depicted in the table below, was prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 95

¹H-NMR (CDCl₃, 400 MHz) δ 8.69 (d, J = 9.2 Hz, 1H), 8.10 (s, 1H), 8.04(s, 1H), 7.83~7.89 (m, 4H), 7.70 (d, J = 9.6 Hz, 2H), 7.58 (s, 1H),7.13~7.18 (m, 4H), 5.84 (d, J = 4.0 Hz, 1H), 3.23 (s, 3H), 2.91 (d, J =4.8 Hz, 3H), 2.81 (s, 3H). 588

Example 16 Preparation of Compound 96

Step 1—Synthesis of 3-chloro-6-hydrazinylpyridazine

To a degassed solution of 3,6-dichloropyridazine (18 g, 120 mmol) andhydrazine (6.4 mL) in 1,4-dioxane (80 mL) was added Et₃N (16.8 mL) underN₂. The mixture was heated to 100° C. overnight. The reaction mixturewas concentrated and then it was poured into ice-water. After filtrated,the solid was collected and dried as the product of3-chloro-6-hydrazinylpyridazine (14.7 g, yield: 84%). ¹H-NMR (DMSO-d₆,400 MHz) δ 8.19 (s, 1H), 7.36 (d, J=9.2 Hz, 1H), 7.05 (d, J=9.2 Hz, 1H),4.34 (s, 2H). MS (M+H)⁺: 145/147.

Step 2—Synthesis ofN′-(6-chloropyridazin-3-yl)-4-(trifluoromethyl)benzohydrazide

A degassed solution of 4-(trifluoromethyl)benzoic acid (1.0 g, 5.26mmol) in SOCl₂ (10 mL) was heated at 100° C. for 2 hours. Afterconcentrated and dissolved in DCM (10 mL), the resulting solution wasadded into a solution of 3-chloro-6-hydrazinylpyridazine (836 mg, 5.79mmol) and Et₃N (1.14 mL) in DCM (10 mL) under N₂ dropwise. Then it wasstirred at 25° C. for 8 hours and then the mixture was diluted with H₂O.After extracted with DCM, the organics were concentrated to afford theproduct of N′-(6-chloropyridazin-3-yl)-4-(trifluoromethyl)benzohydrazide(1.6 g, yield: 96%). ¹H-NMR (DMSO-d₆, 400 MHz) δ 10.83 (s, 1H), 9.35 (s,1H), 8.08 (d, J=8.0 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.54 (d, J=9.2 Hz,1H), 7.10 (d, J=9.2 Hz, 1H). MS (M+H)⁺: 317/319.

Step 3—Synthesis of6-chloro-3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine

A stirred solution ofN′-(6-chloropyridazin-3-yl)-4-(trifluoromethyl)benzohydrazide (200 mg,0.63 mmol) in HCOOH (2 mL) under nitrogen was stirred at 100° C. for 5hours and then the solvent was removed in vacuo to give a brown residue.The crude product was washed with NaHCO₃ (aq) and concentrated toobtained the product of6-chloro-3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine(100 mg, 53%) as a brown solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.57 (d, J=8.0Hz, 2H), 8.14 (d, J=9.6 Hz, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.15 (d, =9.6Hz, 1H). MS (M+H)⁺: 299/301.

Step 4—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzofuran-3-carboxamide

To a degassed solution of6-chloro-3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine(80 mg, 0.3 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 100 mg, 0.2 mmol) in 1,4-dioxane (2.0 mL) were addedPd(dppf)Cl₂ (10 mg) and K₃PO₄ (70 mg, 0.4 mmol) under N₂. The mixturewas heated to 100° C. overnight. The reaction mixture was cooled to RTand filtered. The filtrate was washed with H₂O, brine, dried overNa₂SO₄. After concentrated, the residue was purified by prep-HPLC togive2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzofuran-3-carboxamide(20 mg, yield: 17%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.59 (d, J=8.0 Hz, 2H),8.13˜8.22 (m, 3H), 7.84˜7.88 (m, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.60 (s,1H), 7.42˜7.45 (m, 1H), 7.16˜7.20 (m, 2H), 5.80 (s, 1H), 3.25 (s, 3H),2.92 (d, J=4.8 Hz, 3H), 2.86 (s, 3H). MS (M+H)⁺: 639.

Example 17 Preparation of Compound 97

Step 1—Synthesis of2-(5-bromo-2,3-dihydrobenzofuran-7-yl)oxazolo[4,5-b]pyridine

A mixture of 5-bromo-2,3-dihydrobenzofuran-7-carboxylic acid (0.80 g,3.29 mmol), 2-aminopyridin-3-ol (0.40 g, 3.63 mmol) in PPA (6 mL) wasstirred at 140° C. for 2 h. The reaction mixture was added to water andbasified to pH=8, then extracted with ethyl acetate and washed withbrine, dried over Na₂SO₄. After concentrated, the residue was purifiedby column chromatography (PE:EtOAc=1:2) to give the product of2-(5-bromo-2,3-dihydrobenzofuran-7-yl)oxazolo[4,5-b]pyridine (600 mg,yield: 58%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.59 (s, 1H), 8.18 (s, 1H), 7.90(d, J=6.4 Hz, 1H), 7.45 (s, 1H), 7.28˜7.30 (m, 1H), 4.8˜44.88 (m, 2H),3.32˜3.34 (m, 2H). MS (M+H)⁺: 317/319.

Step 2—Synthesis of 2-(5-bromobenzofuran-7-yl)oxazolo[4,5-b]pyridine

To a solution of2-(5-bromo-2,3-dihydrobenzofuran-7-yl)oxazolo[4,5-b]pyridine (400 mg,1.26 mmol) and AIBN (20 mg, 0.12 mmol) in CCl₄ (2 mL), NBS (250 mg, 1.4mmol) was added. The reaction mixture was refluxed for 2 hours. Thereaction mixture was quenched with water and the mixture was extractedwith CH₂Cl₂. The organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by columnchromatography (PE:EtOAc=5:1) to give the product of2-(5-bromobenzofuran-7-yl)oxazolo[4,5-b]pyridine (300 mg, yield: 76%).¹H-NMR (CDCl₃, 400 MHz) δ 8.58 (d, J=4.0 Hz, 1H), 8.33 (d, J=1.6 Hz,1H), 7.88˜7.91 (m, 2H), 7.81˜7.83 (m, 1H), 7.28˜7.31 (m, 1H), 6.79 (d,J=2.0 Hz, 1H). MS (M+H)⁺: 315/317.

Step 3—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-7′-(oxazolo[4,5-b]pyridin-2-yl)-[5,5′-bibenzofuran]-3-carboxamide

To a stirring solution of2-(5-bromobenzofuran-7-yl)oxazolo[4,5-b]pyridine (80 mg, 0.25 mmol) indioxane (2 mL), K₃PO₄.3H₂O (160 mg, 0.6 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 100 mg, 0.20 mmol) were added, then Pd(dppf) Cl₂ (5 mg) wasadded under N₂ protection, and the mixture was stirred at 80° C.overnight. The mixture was concentrated in vacuo. The residue waspurified by prep-HPLC to give the product of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-7′-(oxazolo[4,5-b]pyridin-2-yl)-[5,5′-bibenzofuran]-3-carboxamide(35 mg, yield: 30%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.2˜38.51 (m, 1H), 8.23(d, J=1.2 Hz, 1H), 7.83˜7.88 (m, 6H), 7.55 (s, 1H), 7.24˜7.27 (m, 1H),7.0˜87.13 (m, 2H), 6.23˜6.24 (br s, 1H), 3.08 (s, 3H), 2.94 (d, J=4.8Hz, 3H), 2.65 (s, 3H). MS (M+H)⁺: 611.

Compound 98, depicted in the table below, was prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 98

¹H-NMR (CDCl₃, 400 MHz) δ 8.24 (d, J = 1.2 Hz, 1H), 7.85~7.92 (m, 5H),7.59 (s, 1H), 7.40~7.43 (m, 1H), 7.28~7.29 (m, 1H), 7.15~7.19 (m, 2H),7.06~7.13 (m, 1H), 6.90 (d, J = 2.4 Hz, 1H), 5.84 (s, 1H), 3.10 (s, 3H),2.93 (d, J = 4.8 Hz, 3H), 2.64 (s, 3H). 628

Example 18 Preparation of Compound 99

Step 1—Synthesis of 6,8-dibromo-2-methylimidazo[1,2-a]pyridine

A mixture of 3,5-dibromopyridin-2-amine (1.8 g, 7 mmol) and1-chloropropan-2-one (1.5 g, 16 mmol) in EtOH (20 mL) was stirred at100° C. for 48 h. The mixture was then concentrated in vacuum. Theresidue was purified by chromatography (DCM:MeOH=10:1) to give thedesired product of 6,8-dibromo-2-methylimidazo[1,2-a]pyridine (1 g,yield: 48.3%). ¹H-NMR (DMSO-d₆, 400 MHz) δ 8.84 (s, 1H), 7.76 (s, 1H),7.69 (s, 1H), 2.31 (s, 3H). MS (M+H)⁺: 289/291/293.

Step 2—Synthesis of6-bromo-8-(1H-indol-2-yl)-2-methylimidazo[1,2-a]pyridine

To a degassed solution of (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (300 mg, 1.15 mmol),6,8-dibromo-2-methylimidazo[1,2-a]pyridine (1 g, 3.45 mmol) and K₃PO₄(917 mg, 3.45 mmol) in dry DMF (5 mL) was added Pd(dppf)Cl₂ (84 mg, 0.12mmol) under N₂. The mixture was heated to 80° C. and then stirredovernight. The reaction mixture was cooled to RT, diluted with EtOAc andfiltered. The filtrate was washed with H₂O, brine, dried over Na₂SO₄.After concentrated, the residue was purified by prep-TLC (PE:EtOAc=2:1)to give the product of6-bromo-8-(1H-indol-2-yl)-2-methylimidazo[1,2-a]pyridine (150 mg, yield:30.7%). ¹H-NMR (CDCl₃, 400 MHz) δ 11.86 (s, 1H), 8.02 (d, J=1.6 Hz, 1H),7.66 (d, J=1.6 Hz, 1H), 7.58˜7.60 (m, 1H), 7.47˜7.50 (m, 1H), 7.33˜7.35(m, 1H), 7.27 (s, 1H), 7.03˜7.17 (m, 1H), 6.49 (t, J=2.0 Hz, 1H), 2.46(s, 3H). MS (M+H)⁺: 326/328.

Step 3—Synthesis of5-(8-(1H-indol-2-yl)-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 177 mg, 0.35 mmol),6-bromo-8-(1H-indol-2-yl)-2-methylimidazo[1,2-a]pyridine (150 mg, 0.46mmol) and K₃PO₄ (281 mg, 1.06 mmol) in dioxane/H₂O (1.5 mL/0.4 mL) wereadded Pd₂(dba)₃ (20 mg, 0.02 mmol) and X-phos (17 mg, 0.04 mmol) underN₂. The mixture was heated to 80° C. and then stirred overnight. Thereaction mixture was cooled to RT, diluted with EtOAc and filtered. Thefiltrate was washed with H₂O, brine, dried over Na₂SO₄. Afterconcentrated, the residue was purified by prep-TLC (PE:EtOAc=1:1) togive the desired product of5-(8-(1H-indol-2-yl)-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(120 mg, yield: 42%). ¹H-NMR (CDCl₃, 400 MHz) δ 11.97 (s, 1H), 8.13 (d,J 1.2 Hz, 1H), 7.89˜7.93 (m, 3H), 7.90 (d, J 1.2 Hz, 1H), 8.62 (d, J 7.2Hz, 2H), 7.55 (d, J 8.4 Hz, 1H), 7.42 (s, 1H), 7.08˜7.22 (m, 5H), 5.85(d, J=4.8 Hz, 1H), 3.10 (s, 3H), 2.96 (d, J 4.8 Hz, 3H), 2.88 (s, 3H),2.56 (s, 3H). MS (M+H)⁺: 622.

Example 19 Preparation of Compound 100

Step 1—Synthesis of N³-(tert-butyl)-6-chloropyridine-2,3-diamine and6-chloropyridine-2,3-diamine

A mixture of 6-chloro-3-nitropyridin-2-amine (15 g, 86.4 mmol) andSnCl₂.2H₂O (98 g, 0.43 mol) in ethyl acetate/2-methylpropan-2-ol (450mL/90 mL) was stirred at 60° C. for 1 h. Then NaBH₄ (1.6 g, 43.2 mmol)was added at 60° C. and the resultant mixture was stirred at the sametemperature for another 3 h. Water was added and the mixture wasextracted. The organic layer was washed with NaHCO₃ solution and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (EA:DCM=1:1) to give the product ofN³-(tert-butyl)-6-chloropyridine-2,3-diamine (4.0 g, yield: 30%) and6-chloropyridine-2,3-diamine (5.0 g, yield: 43%). ¹H-NMR (DMSO-d₆, 400MHz) δ 6.84 (d, J=8.0 Hz, 1H), 6.37 (d, J=8.0 Hz, 1H), 5.99 (s, 2H),3.98 (s, 1H), 1.20 (s, 9H), MS (M+H)⁺: 200/202. ¹H-NMR (DMSO-d₆, 400MHz) δ 6.65 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.0 Hz, 1H), 5.76 (s, 2H),4.73 (s, 2H), MS (M+H)⁺: 144/146.

Step 2—Synthesis of1-(tert-butyl)-5-chloro-2-phenyl-1H-imidazo[4,5-b]pyridine

A mixture of benzaldehyde (266 mg, 2.5 mmol) in MeOH (5 mL) was addeddropwise to a mixture of N³-(tert-butyl)-6-chloropyridine-2,3-diamine(500 mg, 2.5 mmol) and NaHSO₃ (313 mg, 3.0 mmol) in MeOH (30 mL). Themixture was stirred at 100° C. for 2 h. The mixture was filtered. Thefiltrate was concentrated and the residue was washed with water andCH₂Cl₂, then the residue was dried to give the product of1-(tert-butyl)-5-chloro-2-phenyl-1H-imidazo[4,5-b]pyridine (300 mg,yield: 42%) which was directly in the next step without furtherpurification.

Step 3—Synthesis of5-(1-(tert-butyl)-2-phenyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 176 mg, 0.35 mmol),1-(tert-butyl)-5-chloro-2-phenyl-1H-imidazo[4,5-b]pyridine (150 mg, 0.52mmol) and K₃PO₄.3H₂O (280 mg, 1.10 mmol) in dioxane/H₂O (1 mL/0.1 mL)were added Pd₂(dba)₃ (20 mg, 0.02 mmol) and X-phos (17 mg, 0.04 mmol)under N₂. The mixture was heated to 80° C. and then stirred overnight.The reaction mixture was cooled to RT, diluted with EtOAc and filtered.The filtrate was washed with H₂O, brine, dried over Na₂SO₄. Afterconcentrated, the residue was purified by prep-TLC (PE:EtOAc=1:1) togive the desired product of5-(1-(tert-butyl)-2-phenyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(100 mg, yield: 46%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.0˜68.08 (m, 1H),7.92˜7.99 (m, 3H), 7.52˜7.57 (m, 2H), 7.33˜7.40 (m, 5H), 7.08˜7.12 (m,2H), 6.68 (s, 1H), 3.11 (s, 3H), 2.93 (s, 3H), 2.84 (s, 3H), 1.58 (s,9H). MS (M+H)⁺: 626.

Compounds 101 and 102, depicted in the table below, were prepared usingthe method described above and substituting the appropriate reactantsand reagents.

MS Compound Structure NMR (M + H)⁺ 101

¹H-NMR (CDCl₃, 400 MHz) δ 8.16~8.18 (s, 2H), 8.09~8.11 (m, 2H),7.94~8.00 (m, 3H), 7.44~7.51 (m, 5H), 7.10~7.18 (m, 3H), 3.31 (s, 3H),3.02 (d, J = 4.4 Hz, 3H), 2.83 (s, 3H). 570 102

¹H-NMR (Methanol-d4, 400 MHz) δ 8.12~8.14 (m, 2H), 7.89~7.97 (m, 4H),7.82~7.85 (m, 1H), 7.67~7.73 (m, 5H), 7.24~7.29 (m, 2H), 3.15 (s, 3H),2.96 (s, 3H), 2.93 (s, 3H). 569

Example 20 Preparation of Compound 103

Step 1—Synthesis of 5-bromo-2-phenyl-1H-indole

To a suspension of acetophenone (1.03 g, 5.0 mmol) and4-bromophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) in ethanol (5mL) was added a few drops of glacial acetic acid. The reaction wasstirred at 80° C. for 2 h. Solvent was evaporated to yield thephenylhydrazone intermediate, which was added to polyphosphoric acid (20g). The reaction mixture was stirred at 120° C. for 2 h. The mixture waspoured into crashed ice and then neutralized with 1 M NaOH and extractedwith CH₂Cl₂. The combined organic extracts were washed with water, driedover anhydrous Na₂SO₄, and evaporated to give 5-bromo-2-phenyl-1H-indole(0.92 g, 68%) as a pale yellow solid. ¹H-NMR (CDCl₃, 400 MHz) δ 8.29 (s,1H), 7.68 (s, 1H), 7.57˜7.62 (m, 2H), 7.36˜7.40 (m, 2H), 7.23˜7.29 (m,1H), 7.18˜7.20 (m, 2H), 6.69 (s, 1H). MS (M+H)⁺: 272/274.

Step 2—Synthesis of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(2-phenyl-1H-indol-5-yl)benzofuran-3-carboxamide

To a degassed solution of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 147 mg, 0.29 mmol), 5-bromo-2-phenyl-1H-indole (80 mg, 0.29mmol) and K₃PO₄.3H₂O (124 mg, 0.58 mmol) in DMF (3 mL) were addedPd(dppf) Cl₂ (10 mg) under N₂. The mixture was heated to 90° C. for 3hours. The reaction mixture was cooled to RT, diluted with EtOAc andfiltered. The filtrate was washed with H₂O, brine, dried over Na₂SO₄.After concentrated, the residue was purified by prep-HPLC to give thedesired product of2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(2-phenyl-1H-indol-5-yl)benzofuran-3-carboxamide(30 mg, yield: 17.9%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.49 (s, 1H), 7.9˜27.95(m, 2H), 7.78 (s, 1H), 7.62 (s, 1H), 7.53˜7.55 (m, 2H), 7.30˜7.36 (m,3H), 7.20˜7.24 (m, 2H), 7.14˜7.18 (m, 2H), 7.04˜7.06 (m, 1H), 6.52 (s,1H), 5.82 (d, J=4.8 Hz, 1H), 3.00 (s, 3H), 2.88 (d, J=4.8 Hz, 3H), 2.29(s, 3H). MS (M+H)⁺: 568.

Example 21 Preparation of Compound 104

Step 1—Synthesis of tert-butyl 5-chloro-1H-indole-1-carboxylate

To a solution of 5-chloro-1H-indole (1.5 g, 9.9 mmol) and DMAP (120 mg,0.99 mmol) in dry DCM (20 mL) Boc₂O (3.24 g) was added dropwise, andthen the mixture was stirred at 25° C. The mixture was stirred to at 25°C. for overnight. The solvent was removed by vacuum. The residue waspurified by column chromatography (PE:EA=50:1) to give the product oftert-butyl 5-chloro-1H-indole-1-carboxylate (2.4 g, yield: 96%). ¹H-NMR(CDCl₃, 400 MHz) δ 7.98 (d, J=8.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H), 7.1˜67.19 (m, 1H), 6.41 (d, J=4.0 Hz, 1H), 1.58 (s,12H). MS (M+H)⁺: 252.

Step 2—Synthesis of tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

To a degassed solution of tert-butyl 5-chloro-1H-indole-1-carboxylate(1.0 g, 3.97 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.11 g,4.37 mmol) in dry DMF (10 mL) was added Pd(dba)₃ (10 mg), x-Phos (10 mg)and AcOK (780 mg, 7.95 mmol) under N₂. The mixture was heated to 100° C.and then stirred overnight. The reaction mixture was cooled to RT andfiltered. The filtrate was washed with EA, brine, dried over Na₂SO₄.After concentrated, the residue was purified by column (PE:EA=50:1) togive the product of tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(1.0 g, yield: 73%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.12 (d, J=8.0 Hz, 1H),8.04 (s, 1H), 7.74 (d, J=12.0 Hz, 1H), 7.54 (d, J=4.0 Hz, 1H), 6.54 (d,J=4.0 Hz, 1H), 1.65 (s, 9H), 1.35 (s, 12H). MS (M+H)⁺: 344.

Step 3—Synthesis of tert-butyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-1H-indole-1-carboxylate

To a degassed solution of tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(0.5 g, 0.88 mmol) and5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(332 mg, 0.96 mmol) in dry DMF (10 mL) was added Pd(dppf)Cl₂ (10 mg) andK₃PO₄ (468 mg, 1.76 mmol) under N₂. The mixture was heated to 100° C.and then stirred overnight. The reaction mixture was cooled to RT andfiltered. The filtrate was washed with EA, brine, dried over Na₂SO₄.After concentrated, the residue was purified by column (PE:EA=2:1) togive the product of tert-butyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-1H-indole-1-carboxylate(400 mg, yield: 76.9%). ¹H-NMR (CDCl₃, 400 MHz) 8.17 (d, J=8.0 Hz, 1H),7.92˜7.96 (m, 2H), 7.78 (s, 1H), 7.60˜7.63 (m, 3H), 7.36 (d, J=1.6 Hz,1H), 7.17 (t, J=8.0 Hz, 2H), 6.58 (d, J=4.0 Hz, 1H), 5.88 (d, J=4.0 Hz,1H), 3.13 (s, 3H), 2.96 (d, J=4.0 Hz, 3H), 2.49 (s, 3H), 1.68 (s, 9H).(M+H)⁺: 592.

Example 22 Preparation of Compound 105

Step 1—Synthesis of 6-bromo-1-(4-fluorophenyl)-1H-indazole

To a solution of 6-bromo-1H-indazole (500 mg, 2.54 mmol) and1-fluoro-4-iodobenzene (845 mg, 3.81 mmol) in Dioxane (10 mL), Cs₂CO₃(2.07 g, 6.35 mmol), CuI (48 mg, 0.25 mmol) andtrans-N,N′-dimethyl-1,2-cyclohexanediamine (50 mg, 0.35 mmol) wereadded. The reaction mixture was stirred at 100° C. overnight. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was purified by column chromatography (PE:EtOAc=20:1) to provide6-bromo-1-(4-fluorophenyl)-1H-indazole (400 mg, yield: 55%).

Step 2—Synthesis of2-(4-fluorophenyl)-5-(1-(4-fluorophenyl)-1H-indazol-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

The procedure of2-(4-fluorophenyl)-5-(1-(4-fluorophenyl)-1H-indazol-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(150 mg, yield 78%) was similar to that of Example 1. ¹H-NMR (CDCl₃, 400MHz) δ 8.23 (s, 1H), 7.95˜7.92 (m, 2H), 7.85 (t, 3H), 7.77˜7.73 (m, 2H),7.60 (s, 1H), 7.30 (dd, J=J₂=1.2 Hz, 1H), 7.24˜7.19 (m, 4H), 5.82 (s,1H), 3.08 (s, 3H), 2.96 (d, J=5.2 Hz, 3H), 2.74 (s, 3H). (M+H)⁺: 587.

Compounds 106-108, depicted in the table below, were prepared using themethod described above and substituting the appropriate reactants andreagents.

MS Compound Structure NMR (M + H)⁺ 106

¹H-NMR (CDCl₃, 400 MHz) δ 8.21 (s, 1H), 7.81~7.92 (m, 5H), 7.73 (d, J =8.0 Hz, 2H), 7.57 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0Hz, 1H), 7.16~7.24 (m, 2H), 5.87 (d, J = 4.0 Hz, 1H), 3.05 (s, 3H), 2.93(d, J = 4.0 Hz, 3H), 2.74 (s, 3H). 604 107

¹H-NMR (CDCl₃, 400 MHz) δ 8.27 (s, 1H), 7.97~8.00 (m, 3H), 7.90~7.94 (m,2H), 7.85~7.88 (m, 2H), 7.77~7.80 (m, 2H), 7.58 (s, 1H), 7.34 (d, J =8.0 Hz, 1H), 7.18~7.23 (m, 2H), 5.87 (br s, 1H), 3.07 (s, 3H), 2.95 (d,J = 4.8 Hz, 3H), 2.81 (s, 3H). 637 108

¹H-NMR (CDCl₃, 400 MHz) δ 8.49~8.52 (m, 2H), 7.95~8.06 (m, 9H), 7.68 (s,1H), 7.37~7.41 (m, 3H), 3.05 (s, 3H), 3.01 (s, 3H), 2.77 (d, J = 4.0 Hz,3H). 594

Example 23 Preparation of Compound 109

Step 1—Synthesis of5-(1-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of5-(6-bromo-4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-2-fluorobenzonitrile(90 mg, 0.28 mmol) (prepared using similar method described inExample 1) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(Compound E, 144 mg, 0.29 mmol) in 1,4-dioxane and H₂O (3.0 mL) wereadded Pd(dppf)Cl₂ (20 mg) and K₂CO₃ (64 mg, 0.4 mmol) under N₂. Themixture was heated at 110° C. overnight. The reaction mixture was cooledto room temperature and filtered. The filtrate was washed with H₂O,brine, dried over Na₂SO₄. After concentrated, the residue was purifiedby prep-TLC to give Compound 32 and5-(1-(3-carbamoyl-4-fluorophenyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(20 mg/30 mg, yield: 12%/17%). ¹H-NMR (CDCl₃, 400 MHz) δ 8.0˜58.08 (m,3H), 7.69 (s, 2H), 7.53 (s, 1H), 7.40 (s, 1H), 7.27 (t, J=8.0 Hz, 1H),7.12 (t, J=8.4 Hz, 2H), 6.95 (s, 1H), 6.87 (d, J=10.8 Hz, 1H), 3.11 (s,3H), 3.07 (d, J=4.4 Hz, 3H), 2.75 (s, 3H), 1.92 (s, 3H). MS (M+H)⁺: 644.¹H-NMR (CDCl₃, 400 MHz) δ 7.9˜27.97 (m, 1H), 7.89˜7.91 (m, 2H), 7.71 (s,1H), 7.51˜7.55 (m, 1H), 7.45 (s, 1H), 7.27˜7.32 (m, 1H), 7.11 (t, J=6.4Hz, 2H), 6.95˜6.98 (m, 2H), 6.76 (d, J=8.0 Hz, 1H), 6.42 (s, 1H), 6.03(s, 1H), 2.94 (d, J=4.8 Hz, 3H), 2.93 (s, 3H), 2.79 (s, 3H), 2.35 (s,3H). MS (M+H)⁺: 662.

Compound 110, depicted in the table below, was prepared using the methoddescribed above and substituting the appropriate reactants and reagents.

MS Compound Structure NMR (M + H)⁺ 110

¹H-NMR (CDCl₃, 400 MHz) δ 8.16 (s, 1H), 8.05 (s, 1H), 7.86~7.89 (m, 2H),7.77 (s, 2H), 7.49 (s, 1H), 7.42 (s, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.13(t, J = 8.8 Hz, 2H), 7.06 (d, J = 10.8 Hz, 1H), 6.72 (d, J = 10.6 Hz,1H), 6.00 (s, 1H), 5.91 (s, 1H), 2.98 (s, 3H), 2.92 (d, J = 4.8 Hz, 3H),2.82 (s, 3H). 648

Example 24 Preparation of Compound 111

Step 1—Synthesis of5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution of 6-bromo-[1,2,4]triazolo[4,3-a]pyridine (177mg, 0.90 mmol) and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(300 mg, 0.60 mmol) in 1,4-dioxane (8 mL) and water (200 μl) was addedK₃PO₄(380 mg, 1.79 mmol) and 1,1′-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride (39 mg, 0.06 mmol) under N₂ protection. Theresulting mixture was heated to 80° C. and stirred at this temperaturefor 2 hours, then heated to 100° C. and stirred for 2 hours. Thereaction was cooled, filtered through a pad of the celite and washedwith ethyl acetate. The combined filtrate was evaporated in vacuo. Theresulting residue was purified using column chromatography (eluted with0-3% MeOH/DCM) to provide 5-([1,2,4]triazolo[4,3-apyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide] (230 mg, yield: 78%).

Step 2 Synthesis of5-(3-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a solution of2-(4-fluorophenyl)-5-(11-fluoropyrido[3′,2′:4,5]pyrimido[1,6-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(210 mg, 0.43 mmol) in DCM (10 ml) and MeOH (200 μl) was added NBS (151mg, 0.85 mmol). The resulting mixture was stirred at RT for 2 hours,then heated to 40° C. and stirred for 2 hours. Concentrated in vacuo.The resulting residue was purified using column chromatography (elutedwith 0-3% MeOH/DCM) to provide5-(3-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (210 mg, yield: 86%).

Step 3 Synthesis of compound 111

To a degassed solution of5-(3-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, 0.14 mmol) and(4-fluorophenyl)boronic acid (29 mg, 0.21 mmol) in 1,4-dioxane (1.5 mL)and water (100 μl) was added K₃PO₄ (89 mg, 0.42 mmol) and1,1′-Bis(di-tert-butylphosphino) ferrocene palladium dichloride (14 mg,0.02 mmol) under N₂ protection. The resulting mixture was heated to 85°C. and stirred at this temperature for 6 hours. The reaction was cooled,filtered through a pad of the celite and washed with ethyl acetate. Thecombined filtrate was evaporated in vacuo. The resulting residue waspurified using preparative TLC (eluted with 3% MeOH/DCM) to provide2-(4-fluorophenyl)-5-(3-(4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(40 mg, yield: 49%).

Example 25 Preparation of Compound 112

Step 1—Synthesis of2-(4-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a degassed solution 6-bromoimidazo[1,2-a]pyridine (118 mg, 0.60 mmol)and2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(300 mg, 0.60 mmol) in 1,4-dioxane (8 mL) and water (200 μl) was addedK₃PO₄(380 mg, 1.79 mmol) and 1,1′-1,1′-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (39 mg, 0.06 mmol) under N₂ protection.The resulting mixture was heated to 80° C. and stirred at thistemperature for 2 hours, then heated to 100° C. and stirred for 2 hours.The reaction was cooled, filtered through a pad of the celite and washedwith ethyl acetate. The combined filtrate was evaporated in vacuo. Theresulting residue was purified using column chromatography (eluted with0-3% MeOH/DCM) to provide2-(4-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(220 mg, yield: 75%).

Step 2 Synthesis of5-(3-bromoimidazo[1,2-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

To a solution of2-(4-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(200 mg, 0.41 mmol) in DMF (5 ml) was added NBS (94 mg, 0.53 mmol). Theresulting mixture was stirred at RT for 2 hours, then treated with waterand extracted with EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting residue waspurified using column chromatography (eluted with 0-3% MeOH/DCM) toprovide5-(3-bromoimidazo[1,2-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(198 mg, yield: 85%).

Step 3 Synthesis of compound 112

To a degassed solution of5-(3-bromoimidazo[1,2-a]pyridin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(50 mg, 0.09 mmol) and (4-fluorophenyl)boronic acid (24 mg, 0.18 mmol)in 1,4-dioxane (1.5 mL) and water (100 μl) was added K₃PO₄ (37 mg, 0.18mmol) and 1,1′-Bis(di-tert-butylphosphino) ferrocene palladiumdichloride (5.7 mg, 0.009 mmol) under N₂ protection. The resultingmixture was heated to 85° C. and stirred at this temperature for 6hours. The reaction was cooled, filtered through a pad of the celite andwashed with ethyl acetate. The combined filtrate was evaporated invacuo. The resulting residue was purified using preparative TLC (elutedwith 3% MeOH/DCM) to provide2-(4-fluorophenyl)-5-(3-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide(20 mg, yield: 39%).

Example 26 Preparation of Compound 113

Step 1

A mixture of 2-bromo-1-(4-fluorophenyl)ethanone (1 g, 4.61 mmol) and6-chloropyridazin-3-amine (0.597 g, 4.61 mmol) in Ethanol (20 mL) washeated to reflux for 1.5 h. The reaction was cooled down. Filtered andgive 6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (400 mg, 1.615mmol, 35.1% yield).

Step 2

A mixture of 6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (79 mg,0.32 mmol),2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(100 mg, 0.26 mmol), K₃PO₄.3H₂O (113 mg, 0.53 mmol),1,1′-bis(di-t-butylphosphino)-ferrocene palladium dichloride (12 mg,0.027 mmol) was allowed to stir in dioxane/H₂O (5 mL, 4/1) at 100° C.overnight. The reaction mixture was cooled to 25° C., diluted with waterand extracted with ethyl acetate. The organic extract was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting residue was purified using prep-HPLC to provide Compound 113(45 mg, yield: 29%).

Example 27 Preparation of Compound 114

A mixture of(E)-2-(4-(tert-butoxy)benzylidene)-5-chlorobenzofuran-3(2H)-one (131 mg,0.4 mmol),2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(100 mg, 0.26 mmol), K₃PO₄.3H₂O (113 mg, 0.53 mmol),1,1′-bis(di-t-butylphosphino)-ferrocene palladium dichloride (12 mg,0.027 mmol) was allowed to stir in dioxane/H₂O (5 mL, 4/1) at 100° C.overnight. The reaction mixture was cooled to 25° C., diluted with waterand extracted with ethyl acetate. The organic extract was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting residue was purified using prep-HPLC to provide Compound 114(35 mg, yield: 20%).

Example 28 Measuring Compound Inhibitory Potency

Measurement of inhibition by compounds was performed using the HCVreplicon system. Several different replicons encoding different HCVgenotypes or mutations were used. In addition, potency measurements weremade using different formats of the replicon assay, including differentways of measurements and different plating formats. See Jan M. Vrolijket al., A replicons-based bioassay for the measurement of interferons inpatients with chronic hepatitis C, 110 J. VIROLOGICAL METHODS 201(2003); Steven S. Carroll et al., Inhibition of Hepatitis C Virus RNAReplication by 2′-Modified Nucleoside Analogs, 278(14) J. BIOLOGICALCHEMISTRY 11979 (2003). However, the underlying principles are common toall of these determinations, and are outlined below.

Stable neomycin phosphotransferase encoding replicons-harboring celllines were used, so all cell lines were maintained under G418 selectionprior to the assay. Potency was determined using a cell ELISA assay withan antibody to the replicons encoded NS3/4a protease. See CaterinaTrozzi et al., In Vitro Selection and Characterization of Hepatitis CVirus Serine Protease Variants Resistant to an Active-Site PeptideInhibitor, 77(6) J. Virol. 3669 (2003). To initiate an assay, repliconcells were plated in the presence of a dilution series of test compoundin the absence of G418. Typically, the assays were performed in a96-well plate formate for manual operation, or a 384-well plate formatfor automated assay. Replicon cells and compound were incubated for 96hours. At the end of the assay, cells were washed free of media andcompound, and the cells were then lysed. RNA was quantified indirectlythrough detection of replicon-encoded NS3/4A protein levels, through anELISA-based assay with an antibody specific for NS3/4A. IC₅₀determinations were calculated as a percentage of a DMSO control byfitting the data to a four-parameter fit function and the data obtainedis provided in the table below.

Data for selected compounds of the present invention was obtained forgenotypes 1a and 1b using this method and is provided in the tablebelow:

1a 1b Compound IC₅₀ (nM) IC₅₀ (nM) 1 16.5 4.6 2 13.2 2.5 3 68 5.8 4 26.52.5 5 2.1 0.8 6 10.6 1.2 7 2.6 2.2 8 27.7 3.9 9 75.8 7.1 10 4 3.6 1138.9 3.5 12 11.7 2.6 13 18.2 3.8 14 2.7 1.2 15 5.5 1.2 16 37.2 4.6 1737.6 12.8 18 16.6 2.1 19 12.8 2.2 20 6.1 2.4 27 25.3 2.9 22 14.4 3.3 2336.7 8.2 24 760.5 82.6 25 585.2 51.1 26 64.7 12.0 27 755 75.7 28 4.2 3.329 5 3.3 30 6.3 2.8 31 3.4 3.1 32 5.3 3.1 33 13.7 8.8 34 24.8 4.3 3535.2 5.9 36 36.2 6.5 37 6.8 4.3 38 629 155 39 1825 82.4 40 338.5 20.2 41118.7 6.7 42 1518 299.2 43 158.1 17.3 44 56.5 7.7 45 94.8 14.4 46 74.510.7 47 2.1 1.5 48 2.6 3.3 49 8.3 3.3 50 3.2 4.1 51 34.6 7.8 52 42.9 7.153 82.0 12.5 54 109.3 14.1 55 152.1 23.8 56 223.8 30.8 57 13.9 3.0 587.2 2.6 59 15.3 5.2 60 45.4 4.4 61 34.2 10.1 62 182.8 22.9 63 23.5 7.264 408.8 76.1 65 1525 114.9 66 2270 225.4 67 131.8 49.8 68 54.2 18.6 69146.8 17.4 70 17.8 11.3 71 21.5 4.5 72 4.9 4.5 73 3.9 3.8 74 20.6 5.4 758 7.3 76 6.8 5.8 77 235.3 32.6 78 19.0 5.3 79 31.4 3.1 80 9.0 6.6 8130.3 5.2 82 23.0 4.9 83 23.6 14.7 84 53.7 8.6 85 459.8 235.4 86 714.5303.7 87 51.5 10.8 88 50.1 7.0 89 7.0 2.7 90 2182 120.3 91 48.2 8.1 9212.9 5.1 93 47.9 7.9 94 75.66 12.3 95 85.9 44.0 96 34.5 16.5 97 2.7 1.398 3.7 4.1 99 3.1 5.2 100 297.2 73.0 101 79.1 17.0 102 14.6 5.1 103 1097100.7 104 179.1 18.9 105 5.2 2.8 016 6.0 6.9 107 8.3 6.1 108 27.6 12.3109 110.0 21.1 110 111.4 13.8 111 4.8 1.9 112 12.4 7.1 113 186.0 14.9114 54.4 37.0

Uses of the Substituted Benzofuran Compounds

The Substituted Benzofuran Compounds are useful in human and veterinarymedicine for treating or preventing a viral infection in a patient. Inone embodiment, the Substituted Benzofuran Compounds can be inhibitorsof viral replication. In another embodiment, the Substituted BenzofuranCompounds can be inhibitors of HCV replication. Accordingly, theSubstituted Benzofuran Compounds are useful for treating viralinfections, such as HCV. In accordance with the invention, theSubstituted Benzofuran Compounds can be administered to a patient inneed of treatment or prevention of a viral infection.

Accordingly, in one embodiment, the invention provides methods fortreating a viral infection in a patient comprising administering to thepatient an effective amount of at least one Substituted BenzofuranCompound or a pharmaceutically acceptable salt thereof

Treatment or Prevention of a Flaviviridae Virus

The Substituted Benzofuran Compounds may be useful for treating orpreventing a viral infection caused by the Flaviviridae family ofviruses.

Examples of Flaviviridae infections include but are not limited to,Japanese encephalitis, Kyasanur Forest disease, Murray Valleyencephalitis, St. Louis encephalitis, Tick-borne encephalitis, West Nileencephalitis, yellow fever and Hepatitis C Virus (HCV) infection.

In one embodiment, the Flaviviridae infection being treated is hepatitisC virus infection.

Treatment or Prevention of HCV Infection

The Substituted Benzofuran Compounds are useful in the inhibition of HCV(e.g., HCV NS5B), the treatment of HCV infection and/or reduction of thelikelihood or severity of symptoms of HCV infection and the inhibitionof HCV viral replication and/or HCV viral production in a cell-basedsystem. For example, the Substituted Benzofuran Compounds are useful intreating infection by HCV after suspected past exposure to HCV by suchmeans as blood transfusion, exchange of body fluids, bites, accidentalneedle stick, or exposure to patient blood during surgery or othermedical procedures.

In one embodiment, the hepatitis C infection is acute hepatitis C. Inanother embodiment, the hepatitis C infection is chronic hepatitis C.

Accordingly, in one embodiment, the invention provides methods fortreating HCV infection in a patient, the methods comprisingadministering to the patient an effective amount of at least oneSubstituted Benzofuran Compound or a pharmaceutically acceptable saltthereof. In a specific embodiment, the amount administered is effectiveto treat or prevent infection by HCV in the patient. In another specificembodiment, the amount administered is effective to inhibit HCV viralreplication and/or viral production in the patient.

The Substituted Benzofuran Compounds are also useful in the preparationand execution of screening assays for antiviral compounds. For examplethe Substituted Benzofuran Compounds are useful for identifyingresistant HCV replicon cell lines harboring mutations within NS5B, whichare excellent screening tools for more powerful antiviral compounds.Furthermore, the Substituted Benzofuran Compounds are useful inestablishing or determining the binding site of other antivirals to theHCV replicase.

The compositions and combinations of the present invention can be usefulfor treating a patient suffering from infection related to any HCVgenotype. HCV types and subtypes may differ in their antigenicity, levelof viremia, severity of disease produced, and response to interferontherapy as described in Holland et al., Pathology, 30(2):192-195 (1998).The nomenclature set forth in Simmonds et al., J Gen Virol,74(Pt11):2391-2399 (1993) is widely used and classifies isolates intosix major genotypes, 1 through 6, with two or more related subtypes,e.g., 1a and 1b. Additional genotypes 7-10 and 11 have been proposed,however the phylogenetic basis on which this classification is based hasbeen questioned, and thus types 7, 8, 9 and 11 isolates have beenreassigned as type 6, and type 10 isolates as type 3 (see Lamballerie etal., J Gen Virol, 78(Pt1):45-51 (1997)). The major genotypes have beendefined as having sequence similarities of between 55 and 72% (mean64.5%), and subtypes within types as having 75%-86% similarity (mean80%) when sequenced in the NS-5 region (see Simmonds et al., J GenVirol, 75(Pt 5):1053-1061 (1994)).

Combination Therapy

In another embodiment, the present methods for treating or preventingHCV infection can further comprise the administration of one or moreadditional therapeutic agents which are not Substituted BenzofuranCompounds.

In one embodiment, the additional therapeutic agent is an antiviralagent.

In another embodiment, the additional therapeutic agent is animmunomodulatory agent, such as an immunosuppressive agent.

Accordingly, in one embodiment, the present invention provides methodsfor treating a viral infection in a patient, the method comprisingadministering to the patient: (i) at least one Substituted BenzofuranCompound, or a pharmaceutically acceptable salt thereof, and (ii) atleast one additional therapeutic agent that is other than a SubstitutedBenzofuran Compound, wherein the amounts administered are togethereffective to treat or prevent a viral infection.

When administering a combination therapy of the invention to a patient,therapeutic agents in the combination, or a pharmaceutical compositionor compositions comprising therapeutic agents, may be administered inany order such as, for example, sequentially, concurrently, together,simultaneously and the like. The amounts of the various actives in suchcombination therapy may be different amounts (different dosage amounts)or same amounts (same dosage amounts). Thus, for non-limitingillustration purposes, a Substituted Benzofuran Compound and anadditional therapeutic agent may be present in fixed amounts (dosageamounts) in a single dosage unit (e.g., a capsule, a tablet and thelike).

In one embodiment, the at least one Substituted Benzofuran Compound isadministered during a time when the additional therapeutic agent(s)exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the at least one Substituted Benzofuran Compoundand the additional therapeutic agent(s) are administered in dosescommonly employed when such agents are used as monotherapy for treatinga viral infection.

In another embodiment, the at least one Substituted Benzofuran Compoundand the additional therapeutic agent(s) are administered in doses lowerthan the doses commonly employed when such agents are used asmonotherapy for treating a viral infection.

In still another embodiment, the at least one Substituted BenzofuranCompound and the additional therapeutic agent(s) act synergistically andare administered in doses lower than the doses commonly employed whensuch agents are used as monotherapy for treating a viral infection.

In one embodiment, the at least one Substituted Benzofuran Compound andthe additional therapeutic agent(s) are present in the same composition.In one embodiment, this composition is suitable for oral administration.In another embodiment, this composition is suitable for intravenousadministration. In another embodiment, this composition is suitable forsubcutaneous administration. In still another embodiment, thiscomposition is suitable for parenteral administration.

Viral infections and virus-related disorders that can be treated orprevented using the combination therapy methods of the present inventioninclude, but are not limited to, those listed above.

In one embodiment, the viral infection is HCV infection.

The at least one Substituted Benzofuran Compound and the additionaltherapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of therapy without reducing theefficacy of therapy.

In one embodiment, the administration of at least one SubstitutedBenzofuran Compound and the additional therapeutic agent(s) may inhibitthe resistance of a viral infection to these agents.

Non-limiting examples of additional therapeutic agents useful in thepresent compositions and methods include an interferon, animmunomodulator, a viral replication inhibitor, an antisense agent, atherapeutic vaccine, a viral polymerase inhibitor, a nucleosideinhibitor, a viral protease inhibitor, a viral helicase inhibitor, avirion production inhibitor, a viral entry inhibitor, a viral assemblyinhibitor, an antibody therapy (monoclonal or polyclonal), and any agentuseful for treating an RNA-dependent polymerase-related disorder.

In one embodiment, the additional therapeutic agent is a viral proteaseinhibitor.

In another embodiment, the additional therapeutic agent is a viralreplication inhibitor.

In another embodiment, the additional therapeutic agent is an HCV NS3protease inhibitor.

In still another embodiment, the additional therapeutic agent is an HCVNS5B polymerase inhibitor.

In another embodiment, the additional therapeutic agent is a nucleosideinhibitor.

In another embodiment, the additional therapeutic agent is aninterferon.

In yet another embodiment, the additional therapeutic agent is an HCVreplicase inhibitor.

In another embodiment, the additional therapeutic agent is an antisenseagent.

In another embodiment, the additional therapeutic agent is a therapeuticvaccine.

In a further embodiment, the additional therapeutic agent is a virionproduction inhibitor.

In another embodiment, the additional therapeutic agent is an antibodytherapy.

In another embodiment, the additional therapeutic agent is an HCV NS2inhibitor.

In still another embodiment, the additional therapeutic agent is an HCVNS4A inhibitor.

In another embodiment, the additional therapeutic agent is an HCV NS4Binhibitor.

In another embodiment, the additional therapeutic agent is an HCV NS5Ainhibitor

In yet another embodiment, the additional therapeutic agent is an HCVNS3 helicase inhibitor.

In another embodiment, the additional therapeutic agent is an HCV IRESinhibitor.

In another embodiment, the additional therapeutic agent is an HCV p7inhibitor.

In a further embodiment, the additional therapeutic agent is an HCVentry inhibitor.

In another embodiment, the additional therapeutic agent is an HCVassembly inhibitor.

In one embodiment, the additional therapeutic agents comprise a viralprotease inhibitor and a viral polymerase inhibitor.

In still another embodiment, the additional therapeutic agents comprisea viral protease inhibitor and an immunomodulatory agent.

In yet another embodiment, the additional therapeutic agents comprise apolymerase inhibitor and an immunomodulatory agent.

In another embodiment, the additional therapeutic agents comprise aviral protease inhibitor and a nucleoside.

In another embodiment, the additional therapeutic agents comprise animmunomodulatory agent and a nucleoside.

In one embodiment, the additional therapeutic agents comprise an HCVprotease inhibitor and an HCV polymerase inhibitor.

In another embodiment, the additional therapeutic agents comprise anucleoside and an HCV NS5A inhibitor.

In another embodiment, the additional therapeutic agents comprise aviral protease inhibitor, an immunomodulatory agent and a nucleoside.

In a further embodiment, the additional therapeutic agents comprise aviral protease inhibitor, a viral polymerase inhibitor and animmunomodulatory agent.

In another embodiment, the additional therapeutic agent is ribavirin.

HCV polymerase inhibitors useful in the present compositions and methodsinclude, but are not limited to, VP-19744 (Wyeth/ViroPharma), PSI-7851(Pharmasset), RG7128 (Roche/Pharmasset), PSI-7977 (Pharmasset), PSI-938(Pharmasset), PSI-879 (Pharmasset), PSI-661 (Pharmasset),PF-868554/filibuvir (Pfizer), VCH-759/VX-759 (ViroChem Pharma/Vertex),HCV-371 (Wyeth/VirroPharma), HCV-796 (Wyeth/ViroPharma), IDX-184(Idenix), IDX-375 (Idenix), NM-283 (Idenix/Novartis), GL-60667(Genelabs), JTK-109 (Japan Tobacco), PSI-6130 (Pharmasset), R1479(Roche), R-1626 (Roche), R-7128 (Roche), MK-0608 (Isis/Merck), INX-8014(Inhibitex), INX-8018 (Inhibitex), INX-189 (Inhibitex), GS 9190(Gilead), A-848837 (Abbott), ABT-333 (Abbott), ABT-072 (Abbott),A-837093 (Abbott), BI-207127 (Boehringer-Ingelheim), BILB-1941(Boehringer-Ingelheim), MK-3281 (Merck), VCH-222/VX-222(ViroChem/Vertex), VCH-916 (ViroChem), VCH-716(ViroChem), GSK-71185(Glaxo SmithKline), ANA598 (Anadys), GSK-625433 (Glaxo SmithKline),XTL-2125 (XTL Biopharmaceuticals), and those disclosed in Ni et al.,Current Opinion in Drug Discovery and Development, 7(4):446 (2004); Tanet al., Nature Reviews, 1:867 (2002); and Beaulieu et al., CurrentOpinion in Investigational Drugs, 5:838 (2004).

Additional HCV polymerase inhibitors useful in the present compositionsand methods include, but are not limited to, nucleoside compounds suchas those disclosed in

Other HCV polymerase inhibitors useful in the present compositions andmethods include, but are not limited to, those disclosed inInternational Publication Nos. WO 08/082484, WO 08/082488, WO 08/083351,WO 08/136815, WO 09/032116, WO 09/032123, WO 09/032124 and WO 09/032125.

Interferons useful in the present compositions and methods include, butare not limited to, interferon alfa-2a, interferon alfa-2b, interferonalfacon-1 and PEG-interferon alpha conjugates. “PEG-interferon alphaconjugates” are interferon alpha molecules covalently attached to a PEGmolecule. Illustrative PEG-interferon alpha conjugates includeinterferon alpha-2a (Roferon™, Hoffman La-Roche, Nutley, N.J.) in theform of pegylated interferon alpha-2a (e.g., as sold under the tradename Pegasys™), interferon alpha-2b (Intron™ from Schering-PloughCorporation) in the form of pegylated interferon alpha-2b (e.g., as soldunder the trade name PEG-Intron™ from Schering-Plough Corporation),interferon alpha-2b-XL (e.g., as sold under the trade name PEG-Intron™),interferon alpha-2c (Berofor Alpha™ Boehringer Ingelheim, Ingelheim,Germany), PEG-interferon lambda (Bristol-Myers Squibb and ZymoGenetics),interferon alfa-2b alpha fusion polypeptides, interferon fused with thehuman blood protein albumin (Albuferon™, Human Genome Sciences), OmegaInterferon (Intarcia), Locteron controlled release interferon(Biolex/OctoPlus), Biomed-510 (omega interferon), Peg-IL-29(ZymoGenetics), Locteron CR (Octoplus), R-7025 (Roche), IFN-α-2b-XL(Flamel Technologies), belerofon (Nautilus) and consensus interferon asdefined by determination of a consensus sequence of naturally occurringinterferon alphas (Infergen™, Amgen, Thousand Oaks, Calif.).

Examples of viral protease inhibitors useful in the present compositionsand methods include, but are not limited to, an HCV protease inhibitor.

HCV protease inhibitors useful in the present compositions and methodsinclude, but are not limited to, those disclosed in U.S. Pat. Nos.7,494,988, 7,485,625, 7,449,447, 7,442,695, 7,425,576, 7,342,041,7,253,160, 7,244,721, 7,205,330, 7,192,957, 7,186,747, 7,173,057,7,169,760, 7,012,066, 6,914,122, 6,911,428, 6,894,072, 6,846,802,6,838,475, 6,800,434, 6,767,991, 5,017,380, 4,933,443, 4,812,561 and4,634,697; U.S. Patent Publication Nos. US20020068702, US20020160962,US20050119168, US20050176648, US20050209164, US20050249702 andUS20070042968; and International Publication Nos. WO 03/006490, WO03/087092, WO 04/092161 and WO 08/124148.

Additional HCV protease inhibitors useful in the present compositionsand methods include, but are not limited to, VX-950 (Telaprevir,Vertex), VX-500 (Vertex), VX-813 (Vertex), VBY-376 (Virobay), BI-201335(Boehringer Ingelheim), TMC-435 (Medivir/Tibotec), ABT-450(Abbott/Enanta), TMC-435350 (Medivir), RG7227 (Danoprevir,InterMune/Roche), EA-058 (Abbott/Enanta), EA-063 (Abbott/Enanta),GS-9256 (Gilead), IDX-320 (Idenix), ACH-1625 (Achillion), ACH-2684(Achillion), GS-9132 (Gilead/Achillion), ACH-1095 (Gilead/Achillon),IDX-136 (Idenix), IDX-316 (Idenix), ITMN-8356 (InterMune), ITMN-8347(InterMune), ITMN-8096 (InterMune), ITMN-7587 (InterMune), BMS-650032(Bristol-Myers Squibb), VX-985 (Vertex) and PHX1766 (Phenomix).

Further examples of HCV protease inhibitors useful in the presentcompositions and methods include, but are not limited to, thosedisclosed in Landro et al., Biochemistry, 36(31):9340-9348 (1997);Ingallinella et al., Biochemistry, 37(25):8906-8914 (1998);Llinàs-Brunet et al., Bioorg Med Chem Lett, 8(13):1713-1718 (1998);Martin et al., Biochemistry, 37(33):11459-11468 (1998); Dimasi et al., JVirol, 71(10):7461-7469 (1997); Martin et al., Protein Eng,10(5):607-614 (1997); Elzouki et al., J Hepat, 27(1):42-48 (1997);BioWorld Today, 9(217):4 (Nov. 10, 1998); U.S. Patent Publication Nos.US2005/0249702 and US 2007/0274951; and International Publication Nos.WO 98/14181, WO 98/17679, WO 98/17679, WO 98/22496 and WO 99/07734 andWO 05/087731.

Further examples of HCV protease inhibitors useful in the presentcompositions and methods include, but are not limited to, the followingcompounds:

and pharmaceutically acceptable salts thereof.

Viral replication inhibitors useful in the present compositions andmethods include, but are not limited to, HCV replicase inhibitors, IRESinhibitors, NS4A inhibitors, NS3 helicase inhibitors, NS5A inhibitors,NS5B inhibitors, ribavirin, AZD-2836 (Astra Zeneca), viramidine, A-831(Arrow Therapeutics), EDP-239 (Enanta), ACH-2928 (Achillion), GS-5885(Gilead); an antisense agent or a therapeutic vaccine.

Viral entry inhibitors useful as second additional therapeutic agents inthe present compositions and methods include, but are not limited to,PRO-206 (Progenics), REP-9C (REPICor), SP-30 (Samaritan Pharmaceuticals)and ITX-5061 (iTherx).

HCV NS4A inhibitors useful in the useful in the present compositions andmethods include, but are not limited to, those disclosed in U.S. Pat.Nos. 7,476,686 and 7,273,885; U.S. Patent Publication No. US20090022688;and International Publication Nos. WO 2006/019831 and WO 2006/019832.Additional HCV NS4A inhibitors useful as second additional therapeuticagents in the present compositions and methods include, but are notlimited to, AZD2836 (Astra Zeneca), ACH-1095 (Achillion) and ACH-806(Achillion).

HCV NS5A inhibitors useful in the present compositions and methodsinclude, but are not limited to, ACH-2928 (Achillon), AZD-7295 (AstraZeneca), A-832 (Arrow Therapeutics), PPI-461 (Presidio), PPI-1301(Presidio), GS-5885 (Gilead) and BMS-790052 (Bristol-Myers Squibb).

HCV replicase inhibitors useful in the present compositions and methodsinclude, but are not limited to, those disclosed in U.S. PatentPublication No. US20090081636.

Therapeutic vaccines useful in the present compositions and methodsinclude, but are not limited to, IC41 (Intercell Novartis), CSL123(Chiron/CSL), GI 5005 (Globeimmune), TG-4040 (Transgene), GNI-103(GENimmune), Hepavaxx C (ViRex Medical), ChronVac-C (Inovio/Tripep),PeviPRO™ (Pevion Biotect), HCV/MF59 (Chiron/Novartis), MBL-HCV1(MassBiologics), GI-5005 (GlobeImmune), CT-011 (CureTech/Teva) andCivacir (NABI).

Examples of further additional therapeutic agents useful in the presentcompositions and methods include, but are not limited to, Ritonavir(Abbott), TT033 (Benitec/Tacere Bio/Pfizer), Sirna-034 (SirnaTherapeutics), GNI-104 (GENimmune), GI-5005 (GlobeImmune), IDX-102(Idenix), Levovirin™ (ICN Pharmaceuticals, Costa Mesa, Calif.); Humax(Genmab), ITX-2155 (Ithrex/Novartis), PRO 206 (Progenics), HepaCide-I(NanoVirocides), MX3235 (Migenix), SCY-635 (Scynexis); KPE02003002(Kemin Pharma), Lenocta (VioQuest Pharmaceuticals), IET—InterferonEnhancing Therapy (Transition Therapeutics), Zadaxin (SciClone Pharma),VP 50406™ (Viropharma, Incorporated, Exton, Pa.); Taribavirin (ValeantPharmaceuticals); Nitazoxanide (Romark); Debio 025 (Debiopharm); GS-9450(Gilead); PF-4878691 (Pfizer); ANA773 (Anadys); SCV-07 (SciClonePharmaceuticals); NIM-881 (Novartis); ISIS 14803™ (ISIS Pharmaceuticals,Carlsbad, Calif.); Heptazyme™ (Ribozyme Pharmaceuticals, Boulder,Colo.); Thymosin™ (SciClone Pharmaceuticals, San Mateo, Calif.);Maxamine™ (Maxim Pharmaceuticals, San Diego, Calif.); NKB-122 (JenKenBioscience Inc., North Carolina); Alinia (Romark Laboratories), INFORM-1(a combination of R7128 and ITMN-191); and mycophenolate mofetil(Hoffman-LaRoche, Nutley, N.J.).

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention ofHCV infection can be determined by the attending clinician, taking intoconsideration the approved doses and dosage regimen in the packageinsert; the age, sex and general health of the patient; and the type andseverity of the viral infection or related disease or disorder. Whenadministered in combination, the Substituted Benzofuran Compound(s) andthe other agent(s) can be administered simultaneously (i.e., in the samecomposition or in separate compositions one right after the other) orsequentially. This particularly useful when the components of thecombination are given on different dosing schedules, e.g., one componentis administered once daily and another component is administered everysix hours, or when the preferred pharmaceutical compositions aredifferent, e.g., one is a tablet and one is a capsule. A kit comprisingthe separate dosage forms is therefore advantageous.

Generally, a total daily dosage of the at least one SubstitutedBenzofuran Compound(s) alone, or when administered as combinationtherapy, can range from about 1 to about 2500 mg per day, althoughvariations will necessarily occur depending on the target of therapy,the patient and the route of administration. In one embodiment, thedosage is from about 10 to about 1000 mg/day, administered in a singledose or in 2-4 divided doses. In another embodiment, the dosage is fromabout 1 to about 500 mg/day, administered in a single dose or in 2-4divided doses. In still another embodiment, the dosage is from about 1to about 100 mg/day, administered in a single dose or in 2-4 divideddoses. In yet another embodiment, the dosage is from about 1 to about 50mg/day, administered in a single dose or in 2-4 divided doses. Inanother embodiment, the dosage is from about 500 to about 1500 mg/day,administered in a single dose or in 2-4 divided doses. In still anotherembodiment, the dosage is from about 500 to about 1000 mg/day,administered in a single dose or in 2-4 divided doses. In yet anotherembodiment, the dosage is from about 100 to about 500 mg/day,administered in a single dose or in 2-4 divided doses.

In one embodiment, when the additional therapeutic agent is INTRON-Ainterferon alpha 2b (commercially available from Schering-Plough Corp.),this agent is administered by subcutaneous injection at 3MIU(12 mcg)/0.5mL/TIW for 24 weeks or 48 weeks for first time treatment.

In another embodiment, when the additional therapeutic agent isPEG-INTRON interferon alpha 2b pegylated (commercially available fromSchering-Plough Corp.), this agent is administered by subcutaneousinjection at 1.5 mcg/kg/week, within a range of 40 to 150 mcg/week, forat least 24 weeks.

In another embodiment, when the additional therapeutic agent is ROFERONA interferon alpha 2a (commercially available from Hoffmann-La Roche),this agent is administered by subcutaneous or intramuscular injection at3MIU(11.1 mcg/mL)/TIW for at least 48 to 52 weeks, or alternatively6MIU/TIW for 12 weeks followed by 3MIU/TIW for 36 weeks.

In still another embodiment, when the additional therapeutic agent isPEGASUS interferon alpha 2a pegylated (commercially available fromHoffmann-La Roche), this agent is administered by subcutaneous injectionat 180 mcg/1 mL or 180 mcg/0.5 mL, once a week for at least 24 weeks.

In yet another embodiment, when the additional therapeutic agent isINFERGEN interferon alphacon-1 (commercially available from Amgen), thisagent is administered by subcutaneous injection at 9 mcg/TIW is 24 weeksfor first time treatment and up to 15 mcg/TIW for 24 weeks fornon-responsive or relapse treatment.

In a further embodiment, when the additional therapeutic agent isRibavirin (commercially available as REBETOL ribavirin fromSchering-Plough or COPEGUS ribavirin from Hoffmann-La Roche), this agentis administered at a daily dosage of from about 600 to about 1400 mg/dayfor at least 24 weeks.

In one embodiment, one or more compounds of the present invention areadministered with one or more additional therapeutic agents selectedfrom: an interferon, an immunomodulator, a viral replication inhibitor,an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor,a nucleoside inhibitor, a viral protease inhibitor, a viral helicaseinhibitor, a viral polymerase inhibitor a virion production inhibitor, aviral entry inhibitor, a viral assembly inhibitor, an antibody therapy(monoclonal or polyclonal), and any agent useful for treating anRNA-dependent polymerase-related disorder.

In another embodiment, one or more compounds of the present inventionare administered with one or more additional therapeutic agents selectedfrom an HCV protease inhibitor, an HCV polymerase inhibitor, an HCVreplication inhibitor, a nucleoside, an interferon, a pegylatedinterferon and ribavirin. The combination therapies can include anycombination of these additional therapeutic agents.

In another embodiment, one or more compounds of the present inventionare administered with one additional therapeutic agent selected from anHCV protease inhibitor, an interferon, a pegylated interferon andribavirin.

In still another embodiment, one or more compounds of the presentinvention are administered with two additional therapeutic agentsselected from an HCV protease inhibitor, an HCV replication inhibitor, anucleoside, an interferon, a pegylated interferon and ribavirin.

In another embodiment, one or more compounds of the present inventionare administered with an HCV protease inhibitor and ribavirin. Inanother specific embodiment, one or more compounds of the presentinvention are administered with a pegylated interferon and ribavirin.

In another embodiment, one or more compounds of the present inventionare administered with three additional therapeutic agents selected froman HCV protease inhibitor, an HCV replication inhibitor, a nucleoside,an interferon, a pegylated interferon and ribavirin.

In one embodiment, one or more compounds of the present invention areadministered with one or more additional therapeutic agents selectedfrom an HCV polymerase inhibitor, a viral protease inhibitor, aninterferon, and a viral replication inhibitor. In another embodiment,one or more compounds of the present invention are administered with oneor more additional therapeutic agents selected from an HCV polymeraseinhibitor, a viral protease inhibitor, an interferon, and a viralreplication inhibitor. In another embodiment, one or more compounds ofthe present invention are administered with one or more additionaltherapeutic agents selected from an HCV polymerase inhibitor, a viralprotease inhibitor, an interferon, and ribavirin.

In one embodiment, one or more compounds of the present invention areadministered with one additional therapeutic agent selected from an HCVpolymerase inhibitor, a viral protease inhibitor, an interferon, and aviral replication inhibitor. In another embodiment, one or morecompounds of the present invention are administered with ribavirin.

In one embodiment, one or more compounds of the present invention areadministered with two additional therapeutic agents selected from an HCVpolymerase inhibitor, a viral protease inhibitor, an interferon, and aviral replication inhibitor.

In another embodiment, one or more compounds of the present inventionare administered with ribavirin, interferon and another therapeuticagent.

In another embodiment, one or more compounds of the present inventionare administered with ribavirin, interferon and another therapeuticagent, wherein the additional therapeutic agent is selected from an HCVpolymerase inhibitor, a viral protease inhibitor, and a viralreplication inhibitor.

In still another embodiment, one or more compounds of the presentinvention are administered with ribavirin, interferon and a viralprotease inhibitor.

In another embodiment, one or more compounds of the present inventionare administered with ribavirin, interferon and an HCV proteaseinhibitor.

In another embodiment, one or more compounds of the present inventionare administered with ribavirin, interferon and boceprevir ortelaprevir.

In a further embodiment, one or more compounds of the present inventionare administered with ribavirin, interferon and an HCV polymeraseinhibitor.

In another embodiment, one or more compounds of the present inventionare administered with pegylated-interferon alpha and ribavirin.

COMPOSITIONS AND ADMINISTRATION

Due to their activity, the Substituted Benzofuran Compounds are usefulin veterinary and human medicine. As described above, the SubstitutedBenzofuran Compounds are useful for treating or preventing HCV infectionin a patient in need thereof.

When administered to a patient, the Substituted Benzofuran Compounds canbe administered as a component of a composition that comprises apharmaceutically acceptable carrier or vehicle. The present inventionprovides pharmaceutical compositions comprising an effective amount ofat least one Substituted Benzofuran Compound and a pharmaceuticallyacceptable carrier. In the pharmaceutical compositions and methods ofthe present invention, the active ingredients will typically beadministered in admixture with suitable carrier materials suitablyselected with respect to the intended form of administration, i.e., oraltablets, capsules (either solid-filled, semi-solid filled or liquidfilled), powders for constitution, oral gels, elixirs, dispersiblegranules, syrups, suspensions, and the like, and consistent withconventional pharmaceutical practices. For example, for oraladministration in the form of tablets or capsules, the active drugcomponent may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier, such as lactose, starch, sucrose, cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, talc,mannitol, ethyl alcohol (liquid forms) and the like. Solid formpreparations include powders, tablets, dispersible granules, capsules,cachets and suppositories. Powders and tablets may be comprised of fromabout 0.5 to about 95 percent inventive composition. Tablets, powders,cachets and capsules can be used as solid dosage forms suitable for oraladministration.

Moreover, when desired or needed, suitable binders, lubricants,disintegrating agents and coloring agents may also be incorporated inthe mixture. Suitable binders include starch, gelatin, natural sugars,corn sweeteners, natural and synthetic gums such as acacia, sodiumalginate, carboxymethylcellulose, polyethylene glycol and waxes. Amongthe lubricants there may be mentioned for use in these dosage forms,boric acid, sodium benzoate, sodium acetate, sodium chloride, and thelike. Disintegrants include starch, methylcellulose, guar gum, and thelike. Sweetening and flavoring agents and preservatives may also beincluded where appropriate.

Liquid form preparations include solutions, suspensions and emulsionsand may include water or water-propylene glycol solutions for parenteralinjection.

Liquid form preparations may also include solutions for intranasaladministration.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize therapeutic effects, i.e., antiviral activity and the like.Suitable dosage forms for sustained release include layered tabletscontaining layers of varying disintegration rates or controlled releasepolymeric matrices impregnated with the active components and shaped intablet form or capsules containing such impregnated or encapsulatedporous polymeric matrices.

In one embodiment, the one or more Substituted Benzofuran Compounds areadministered orally.

In another embodiment, the one or more Substituted Benzofuran Compoundsare administered intravenously.

In one embodiment, a pharmaceutical preparation comprising at least oneSubstituted Benzofuran Compound is in unit dosage form. In such form,the preparation is subdivided into unit doses containing effectiveamounts of the active components.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentcompositions can contain, in one embodiment, from about 0.1% to about99% of the Substituted Benzofuran Compound(s) by weight or volume. Invarious embodiments, the present compositions can contain, in oneembodiment, from about 1% to about 70% or from about 5% to about 60% ofthe Substituted Benzofuran Compound(s) by weight or volume.

The quantity of Substituted Benzofuran Compound in a unit dose ofpreparation may be varied or adjusted from about 1 mg to about 2500 mg.In various embodiment, the quantity is from about 10 mg to about 1000mg, 1 mg to about 500 mg, 1 mg to about 100 mg, and 1 mg to about 100mg.

For convenience, the total daily dosage may be divided and administeredin portions during the day if desired. In one embodiment, the dailydosage is administered in one portion. In another embodiment, the totaldaily dosage is administered in two divided doses over a 24 hour period.In another embodiment, the total daily dosage is administered in threedivided doses over a 24 hour period. In still another embodiment, thetotal daily dosage is administered in four divided doses over a 24 hourperiod.

The amount and frequency of administration of the Substituted BenzofuranCompounds will be regulated according to the judgment of the attendingclinician considering such factors as age, condition and size of thepatient as well as severity of the symptoms being treated. Generally, atotal daily dosage of the Substituted Benzofuran Compounds range fromabout 0.1 to about 2000 mg per day, although variations will necessarilyoccur depending on the target of therapy, the patient and the route ofadministration. In one embodiment, the dosage is from about 1 to about200 mg/day, administered in a single dose or in 2-4 divided doses. Inanother embodiment, the dosage is from about 10 to about 2000 mg/day,administered in a single dose or in 2-4 divided doses. In anotherembodiment, the dosage is from about 100 to about 2000 mg/day,administered in a single dose or in 2-4 divided doses. In still anotherembodiment, the dosage is from about 500 to about 2000 mg/day,administered in a single dose or in 2-4 divided doses.

The compositions of the invention can further comprise one or moreadditional therapeutic agents, selected from those listed above herein.Accordingly, in one embodiment, the present invention providescompositions comprising: (i) at least one Substituted BenzofuranCompound or a pharmaceutically acceptable salt thereof; (ii) one or moreadditional therapeutic agents that are not a Substituted BenzofuranCompound; and (iii) a pharmaceutically acceptable carrier, wherein theamounts in the composition are together effective to treat HCVinfection.

In one embodiment, the present invention provides compositionscomprising a Compound of Formula (I) and a pharmaceutically acceptablecarrier.

In another embodiment, the present invention provides compositionscomprising a Compound of Formula (I), a pharmaceutically acceptablecarrier, and a second therapeutic agent selected from the groupconsisting of HCV antiviral agents, immunomodulators, and anti-infectiveagents.

In another embodiment, the present invention provides compositionscomprising a Compound of Formula (I), a pharmaceutically acceptablecarrier, and wto additional therapeutic agents, each of which areindependently selected from the group consisting of HCV antiviralagents, immunomodulators, and anti-infective agents.

Kits

In one aspect, the present invention provides a kit comprising atherapeutically effective amount of at least one Substituted BenzofuranCompound, or a pharmaceutically acceptable salt, solvate, ester orprodrug of said compound and a pharmaceutically acceptable carrier,vehicle or diluent.

In another aspect the present invention provides a kit comprising anamount of at least one Substituted Benzofuran Compound, or apharmaceutically acceptable salt, solvate, ester or prodrug of saidcompound and an amount of at least one additional therapeutic agentlisted above, wherein the amounts of the two or more active ingredientsresult in a desired therapeutic effect. In one embodiment, the one ormore Substituted Benzofuran Compounds and the one or more additionaltherapeutic agents are provided in the same container. In oneembodiment, the one or more Substituted Benzofuran Compounds and the oneor more additional therapeutic agents are provided in separatecontainers.

The present invention is not to be limited by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited herein, the entire disclosures ofwhich are incorporated herein by reference.

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein: A is:

wherein A can be joined to the benzofuran moiety of formula (I) via anyof group A's ring carbon atoms; L is N or CH; M is N or CH; Q is—CH(R^(4b)); U is —N(R⁵)—, O, S or —C(R^(4b))₂—; V is —N— or—C(R^(4a))—; W is —N— or —C(R⁴)—, or the group —W═V—U— is—NH—C(O)—N(R⁵)— one of Y¹ and Y² is —N— or —C(R¹⁰)—, and the other of Y¹and Y² is a carbon atom and represents the point of attachment of thebenzofuran moiety depicted in formula (I); X and Z are eachindependently —N— or —C(R¹⁰)—; R¹ represents up to 4 optional ringsubstituents, which can be the same or different, and are independentlyselected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, 3 to7-membered monocyclic cycloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)and —CN; R² is —C(O)N(R⁶)(R⁷); R³ is 5 or 6-membered heterocycloalkyl or—N(R⁸)—S(O)_(n)—R⁹, wherein said 5 or 6-membered heterocycloalkyl canoptionally have one of its ring carbon atoms replaced with a carbonylgroup; R⁴ is selected from H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), C₁-C₆ hydroxyalkyl,—C(O)O—(C₁-C₆ alkyl), —(C₁-C₆ alkylene)_(r)-aryl, —(C₁-C₆alkylene)_(r)-(3 to 7-membered monocyclic cycloalkyl), —(C₁-C₆alkylene)_(n)-(4 to 7-membered monocyclic heterocycloalkyl), —(C₁-C₆alkylene)_(n)-(5 or 6-membered monocyclic heteroaryl) and —(C₁-C₆alkylene)_(r)-(9 or 10-membered bicyclic heteroaryl), wherein said arylgroup, said 3 to 7-membered monocyclic cycloalkyl group, said 4 to7-membered monocyclic heterocycloalkyl group, said 5 or 6-memberedmonocyclic heteroaryl group and said 9 or 10-membered bicyclicheteroaryl group can be optionally substituted with up to 3 groups,which can be the same or different, and are selected from halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —S(O)₂—(C₁-C₆ alkyl),—C(O)O—(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl and —CN; R^(4a) is selectedfrom H, C₁-C₆ alkyl, 3 to 7-membered cycloalkyl, phenyl and 5 or6-membered monocyclic heteroaryl, wherein said 3 to 7-memberedcycloalkyl group, said phenyl group and said 5 or 6-membered monocyclicheteroaryl group can be optionally substituted with up to 2 groups,which can be the same or different, and are selected from C₁-C₆ alkyl,C₁-C₆ haloalkyl, halo, —CN, —O—(C₁-C₆ alkyl) and —O—(C₁-C₆ haloalkyl);each occurrence of R^(4b) is independently selected from H, C₁-C₆ alkyl,3 to 7-membered cycloalkyl, phenyl and 5 or 6-membered monocyclicheteroaryl, wherein said 3 to 7-membered cycloalkyl group, said phenylgroup and said 5 or 6-membered monocyclic heteroaryl group can beoptionally substituted with up to 2 groups, which can be the same ordifferent, and are selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, halo,—CN, —O—(C₁-C₆ alkyl) and —O—(C₁-C₆ haloalkyl); each occurrence of R⁵ isindependently selected from H, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl,—C(O)O—(C₁-C₆ alkyl), —(C₁-C₆ alkylene)_(r)-phenyl, —(C₁-C₆alkylene)_(r)-(3 to 7-membered monocyclic cycloalkyl), —(C₁-C₆alkylene)_(r)-(4 to 7-membered monocyclic heterocycloalkyl), —(C₁-C₆alkylene)_(r)-(5 or 6-membered monocyclic heteroaryl) and —(C₁-C₆alkylene)_(r)-(9 or 10-membered bicyclic heteroaryl), wherein saidphenyl group, said 3 to 7-membered monocyclic cycloalkyl group, said 4to 7-membered monocyclic heterocycloalkyl group, said 5 or 6-memberedmonocyclic heteroaryl group and said 9 or 10-membered bicyclicheteroaryl group can be optionally substituted with up to 3 groups,which can be the same or different, and are selected from halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —S(O)₂—C₁-C₆ alkyl,—C(O)O—(C₁-C₆ alkyl), C₁-C₆ hydroxyalkyl and —CN; R⁶ and R⁷ are eachindependently selected from hydrogen, C₁-C₆ alkyl, phenyl, 3 to7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclicheterocycloalkyl and 5 or 6-membered monocyclic heteroaryl; and R⁸ isselected from H, C₁-C₆ alkyl and 3 to 7-membered monocyclic cycloalkyl;R⁹ is selected from H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, 3 to7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclicheterocycloalkyl and 5 or 6-membered monocyclic heteroaryl; eachoccurrence of R¹⁰ is independently selected from H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl) and —CN; eachoccurrence of n is independently 1 or 2; and each occurrence of r isindependently 0 or
 1. 2. The compound of claim 1, wherein A is:


3. The compound of claim 1, wherein A is:


4. The compound of claim 1, wherein R² is —C(O)NH—(C₁-C₆ alkyl).
 5. Thecompound of claim 1, wherein —N(R⁸)—SO₂—R⁹.
 6. The compound of claim 1,wherein R¹ represents a single halo substituent.
 7. The compound ofclaim 2, wherein U is —N(R⁵)—.
 8. The compound of claim 1 having theformula:

or a pharmaceutically acceptable salt thereof, wherein: V is N or—C(R^(4a))—; W is N or —C(R⁴)—; X and Z are each independently N or—C(R¹⁰)—; each occurrence of Y is independently —N— or —C(R¹⁰)—, suchthat one of the two Y groups is a carbon atom and represents the pointof attachment of the benzofuran moiety depicted in formula (I); R¹ is Hor halo; R⁴ is selected from H, pyridyl and phenyl, wherein said phenylgroup can be optionally substituted with C₁-C₆ alkyl, C₁-C₆ haloalkyl orhalo; R^(4a) is selected from H, methyl and phenyl; R⁵ is H; C₁-C₆hydroxyalkyl; —C(O)O-t-butyl; pyridyl; tetrahydropyranyl; phenyl, whichcan be optionally substituted with —O—(C₁-C₆ alkyl), halo, —CN, —CF₃,—OCF₃ or —SO₂CH₃; benzyl, which can be optionally substituted with —CF₃;and pyrrolidinyl, which can be optionally substituted on its ringnitrogen atom with —C(O)O-t-butyl; R⁸ and R⁹ are each C₁-C₆ alkyl; eachoccurrence of R¹⁰ is independently H or halo; and n is 1 or
 2. 9. Thecompound of claim 1, wherein the group:

has the structure:


10. The compound of claim 1, wherein R¹ is F; R² is —C(O)NHCH₃; R³ is—N(CH₃)SO₂CH₃; R⁸ and R⁹ are each methyl; and each occurrence of R¹⁰ isindependently H or F.
 11. The compound of claim 1, having the formula:

or a pharmaceutically acceptable salt thereof, wherein: L is N or CH; Mis N or CH; Q is N or —CH(R^(4b)); V is N or —C(R^(4a))—; R¹ is H orhalo; R⁴ is selected from H, pyridyl and phenyl, wherein said phenylgroup can be optionally substituted with C₁-C₆ alkyl, C₁-C₆ haloalkyl orhalo; R^(4a) is selected from H, methyl and phenyl; R⁵ is H; C₁-C₆hydroxyalkyl; —C(O)O-t-butyl; pyridyl; tetrahydropyranyl; phenyl, whichcan be optionally substituted with —O—(C₁-C₆ alkyl), halo, —CN, —CF₃,—OCF₃ or —SO₂CH₃; benzyl, which can be optionally substituted with —CF₃;and pyrrolidinyl, which can be optionally substituted on its ringnitrogen atom with —C(O)O-t-butyl; and R⁸ and R⁹ are each C₁-C₆ alkyl.12. The compound of claim 1 which is selected from the compoundsnumbered 1-114 in the above specification, or a pharmaceuticallyacceptable salt thereof.
 13. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof. 14.The pharmaceutical composition of claim 12, further comprising a secondtherapeutic agent selected from the group consisting of HCV antiviralagents, immunomodulators, and anti-infective agents.
 15. Thepharmaceutical composition of claim 13, wherein the second therapeuticagent is selected from the group consisting of HCV protease inhibitors,HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
 16. (canceled)17. A method of treating a patient infected with HCV, the methodcomprising administering to the patient the compound of claim 1, or apharmaceutically acceptable salt thereof, in an amount effective toprevent and/or treat infection by HCV in the patient.
 18. The method ofclaim 16, further comprising the step of administeringpegylated-interferon alpha and ribavirin to the patient.